rs149989682

chr16-2317763-T-Achr16-2317763-T-C

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PP3 PP5 BP4 BS2

The NM_001089.3(ABCA3):c.875A>T(p.Glu292Val) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00453 in 1,613,934 control chromosomes in the GnomAD database, including 20 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0030 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0047 (20 hom.)
• Consequence: ABCA3 NM_001089.3 missense, splice_region
• Scores: Splicing: ADA: 0.6552
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:19 U:1
• Conservation: PhyloP100: 7.41

Genes affected

ABCA3 (HGNC:33): (ATP binding cassette subfamily A member 3) The membrane-associated protein encoded by this gene is a member of the superfamily of ATP-binding cassette (ABC) transporters. ABC proteins transport various molecules across extra- and intracellular membranes. ABC genes are divided into seven distinct subfamilies (ABC1, MDR/TAP, MRP, ALD, OABP, GCN20, White). This protein is a member of the ABC1 subfamily. Members of the ABC1 subfamily comprise the only major ABC subfamily found exclusively in multicellular eukaryotes. The full transporter encoded by this gene may be involved in development of resistance to xenobiotics and engulfment during programmed cell death. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_benign. Variant got -3 ACMG points.

• PP3: Multiple lines of computational evidence support a deleterious effect 9: AlphaMissense, BayesDel_noAF, Cadd, dbscSNV1_RF, Eigen, M_CAP, MutationAssessor, PROVEAN, REVEL [when dbscSNV1_ADA, max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster, PrimateAI was below the threshold]
• PP5: Variant 16-2317763-T-A is Pathogenic according to our data. Variant chr16-2317763-T-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 203381.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=8, Likely_pathogenic=8, Uncertain_significance=1}. Variant chr16-2317763-T-A is described in Lovd as [Likely_pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.18085593).. Strength limited to SUPPORTING due to the PP5.
• BS2: High Homozygotes in GnomAdExome at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ABCA3	NM_001089.3	c.875A>T	p.Glu292Val	missense_variant, splice_region_variant	9/33	ENST00000301732.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ABCA3	ENST00000301732.10	c.875A>T	p.Glu292Val	missense_variant, splice_region_variant	9/33	1	NM_001089.3	P1
ABCA3	ENST00000382381.7	c.875A>T	p.Glu292Val	missense_variant, splice_region_variant	9/32	1
ABCA3	ENST00000563623.5	n.1438A>T		splice_region_variant, non_coding_transcript_exon_variant	9/20	1

Frequencies

GnomAD3 genomes AF: 0.00298 AC: 454 AN: 152240 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00101

Gnomad AMI AF: 0.0175

Gnomad AMR AF: 0.00294

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000847

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00501

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00229 AC: 576 AN: 250982 Hom.: 3 AF XY: 0.00238 AC XY: 323 AN XY: 135680

Gnomad AFR exome AF: 0.00117

Gnomad AMR exome AF: 0.00130

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.000555

Gnomad NFE exome AF: 0.00434

Gnomad OTH exome AF: 0.000816

GnomAD4 exome AF: 0.00469 AC: 6862 AN: 1461576 Hom.: 20 Cov.: 32 AF XY: 0.00457 AC XY: 3324 AN XY: 727100

Gnomad4 AFR exome AF: 0.000896

Gnomad4 AMR exome AF: 0.00130

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000696

Gnomad4 FIN exome AF: 0.000693

Gnomad4 NFE exome AF: 0.00584

Gnomad4 OTH exome AF: 0.00397

GnomAD4 genome AF: 0.00298 AC: 454 AN: 152358 Hom.: 0 Cov.: 32 AF XY: 0.00286 AC XY: 213 AN XY: 74500

Gnomad4 AFR AF: 0.00101

Gnomad4 AMR AF: 0.00294

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000847

Gnomad4 NFE AF: 0.00501

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00430 Hom.: 3

Bravo AF: 0.00309

TwinsUK AF: 0.00674 AC: 25

ALSPAC AF: 0.00545 AC: 21

ESP6500AA AF: 0.000910 AC: 4

ESP6500EA AF: 0.00453 AC: 39

ExAC AF: 0.00223 AC: 271

EpiCase AF: 0.00436

EpiControl AF: 0.00403

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:19 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Interstitial lung disease due to ABCA3 deficiency Pathogenic:10

Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Sep 13, 2023	- -
Likely pathogenic, no assertion criteria provided	research	Division of Human Genetics, Children's Hospital of Philadelphia	Jan 08, 2015	The heterozygous variant in the ABCA3 gene (c.875A>T; p.Glu292Val) is considered likely pathogenic. According to Germany et al, the prevalence of this variant is 1:277 (PMID: 18317237) representing the most common ABCA3 variant associated with childhood interstitial lung disease. This variant has been published as a compound heterozygous variant in multiple affected individuals (PMID: 15976379, 22304854) and as a homozygous variant (PMID: 24871971). This variant represents a non-conservative amino acid change at highly conserved amino acid and nucleotide positions while not being located in a functional domain. In the ExAC database there are 271 alleles out of 121060 tested positive for this change. -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Mar 31, 2022	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with pulmonary surfactant metabolism dysfunction 3 (MIM#610921). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from glutamic acid to valine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (654 heterozygotes, 3 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (1 heterozygote, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated ABC2 membrane domain (PDB). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This is the most common ABCA3 disease-causing variant and has been previously reported in >20 patients with variable respiratory disease including paediatric interstitial lung disease (pILD) and idiopathic pulmonary fibrosis, both in the compound heterozygous and homozygous states (ClinVar, PMID: 15976379, 24871971, 25553246, 23625987). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Functional studies demonstrate that this variant causes moderately impaired lipid transport of the protein (PMID: 18676873, 29505158). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Pathogenic, no assertion criteria provided	clinical testing	Seattle Children's Hospital Molecular Genetics Laboratory, Seattle Children's Hospital	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	Across a selection of the available literature the ABCA3 c.875T>A (p.Glu292Val) variant has been reported in a total of 36 patients with various pulmonary disorders, including in ten in a compound heterozygous state with a second missense or intronic variant, and in 26 in a heterozygous state in whom a second variant was not identified (Bullard et al. 2005; Garmany et al. 2008; Copertino et al. 2012; Baekvad-Hansen et al. 2012; Wambach et al. 2012). The variant was reported in three of 638 controls and at a frequency of 0.00454 in the European American population of the Exome Sequencing Project. Functional studies demonstrated that the p.Glu292Val variant exhibits correct cellular localization but moderately impaired transport function, and induces loss of epithelial cell differentiation in lung alveolar epithelia type II cells (Matsumura et al. 2008; Kaltenborn et al. 2011). Based on the collective evidence, the p.Glu292Val variant is classified as pathogenic for pulmonary surfactant metabolism dysfunction. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 04, 2022	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Mar 08, 2023	PS3, PM3, PP3 -
Pathogenic, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	Feb 04, 2019	This ABCA3 variant (rs149989682) is present in large population datasets (gnomAD: 660/282370 total alleles; 0.23%; 3 homozygotes). Five submitters in ClinVar classify this variant as either pathogenic or likely pathogenic. This variant has been reported in numerous affected individuals, both in the compound heterozygous and homozygous state. Multiple functional studies have demonstrated that this variant disrupts ATP hydrolysis and decreases phospholipid transport across the lamellar body membrane. This variant is considered pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 17, 2023	Variant summary: ABCA3 c.875A>T (p.Glu292Val) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0023 in 282370 control chromosomes (gnomAD), predominantly at a frequency of 0.0043 within the Non-Finnish European subpopulation in the gnomAD database, including 3 homozygotes. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 4 fold of the estimated maximal expected allele frequency for a pathogenic variant in ABCA3 causing Pulmonary surfactant metabolism dysfunction phenotype (0.0011), suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. However, c.875A>T has been reported in the literature in multiple homozygous and compound heterozygous individuals affected with various respiratory diseases, including surfactant deficiency syndrome, respiratory distress syndrome and chronic lung disease (e.g. Bullard_2005, Turcu_2013, Akil_2018, Tomer_2021). These data indicate that the variant is likely to be associated with disease. Experimental evidence evaluating an impact on protein function demonstrated the variant is a functional hypomorph exhibiting impaired ATPase activity, lipid transport activity, E-cadherin expression and AT2 cell autophagy (Matsumura_2008, Kaltenborn_2012, Wambach_2016, Wambach_2020, Tomer_2021). Fifteen ClinVar submitters have assessed the variant since 2014: two classified the variant as uncertain significance, five as likely pathogenic, and eight as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genomics Program, Stanford Medicine	Oct 03, 2018	The p.Glu292Val variant in the ABCA3 gene has been previously reported with a second ABCA3 variant in >20 unrelated individuals with a range of pulmonary phenotypes, including respiratory distress, interstitial lung disease, and pulmonary fibrosis, which most commonly presented neonatally or in early childhood (Bullard et al. 2005; Doan et al. 2008; Copertino et al. 2012; Wambach et al. 2012; Turcu et al. 2013; Soares et al. 2013; Epaud et al. 2013; Coghlan et al. 2014; Wambach et al. 2014; Kröner et al. 2017; Akil et al. 2018). Compared to frameshift or nonsense pathogenic variants in the ABCA3 gene, the p.Glu292Val variant has been suggested to result in milder disease severity, with many individuals surviving into childhood or adulthood (Bullard et al. 2005; Copertino et al. 2012; Turcu et al. 2013; Epaud et al. 2013). Functional studies of the p.Glu292Val variant consistently demonstrate a deleterious effect and suggest a partial loss of ABCA3 protein activity (Wambach et al. 2016; Matsumura et al. 2018; Schindlbeck et al. 2018). In a large population database, the variant was identified in 543/126312 (0.43%) European chromosomes, including 3 homozygous individuals (Genome Aggregation Database, http://gnomad.broadinstitute.org). This frequency may suggest reduced penetrance of this allele. Additionally, individuals that are heterozygous for the p.Glu292Val variant are reported to have an increased risk for neonatal respiratory distress (Wambach et al. 2012 and Naderi et al. 2014). These data were assessed using the ACMG/AMP variant interpretation guidelines. In summary, there is sufficient evidence to classify the p.Glu292Val variant as pathogenic for autosomal recessive surfactant metabolism dysfunction, pulmonary, 3. [ACMG evidence codes used: PS3, PS4]. -

not provided Pathogenic:5 Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jan 19, 2015	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	Jan 24, 2022	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2023	ABCA3: PM2, PM3, PP1, PS3:Supporting -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	This sequence change replaces glutamic acid, which is acidic and polar, with valine, which is neutral and non-polar, at codon 292 of the ABCA3 protein (p.Glu292Val). This variant is present in population databases (rs149989682, gnomAD 0.4%), including at least one homozygous and/or hemizygous individual. This missense change has been observed in individual(s) with clinical features of autosomal recessive surfactant deficiency and/or pulmonary surfactant metabolism dysfunction. This variant is frequently observed among individuals with ABCA3 deficiency (PMID: 15976379, 18317237, 23166334, 23625987, 24871971, 29566461, 33110422, 34715861, 35170262, 35626240; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 203381). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects ABCA3 function (PMID: 18676873, 22434821, 27374344, 28034695). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 12, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jan 18, 2023	Variant found to be over-represented in newborns with respiratory distress syndrome suggesting that E292V or its haplotype impart increased genetic risk for RDS (Garmany et al., 2008); Published functional studies demonstrate that the variant contributes to loss of epithelial cell differentiation (Kaltenborn et al., 2012); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 29431110, 17597647, 34662886, 25073622, 18676873, 24136335, 18603241, 22434821, 22866751, 27516224, 23166334, 24871971, 30609409, 25553246, 28034695, 27374344, 29505158, 22800827, 22145626, 18246475, 29569581, 29255193, 22304854, 15976379, 18317237, 29566461, 31980526, 32238781, 31589614, 30755392, 34426522, 33359301, 34132118, 33526094, 32692933, 32196812, 33708521) -

Interstitial lung disease 2 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

Alder lab, University of Pittsburgh

Aug 01, 2022

- -

Diffuse interstitial pulmonary fibrosis;C5680383:Primary interstitial lung disease specific to childhood due to pulmonary surfactant protein anomalies Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Aug 13, 2018

The p.Glu292Val variant in ABCA3 has been reported in 22 compound heterozygous a nd 2 homozygous individuals with various respiratory diseases, including idiopat hic pulmonary fibrosis, desquamative interstitial pneumonitis, neonatal respirat ory failure, and childhood interstitial lung disease (Bullard 2005, Shanklin 200 8, Copertino 2012, Epaud 2014, Coghlan 2014, Wambach 2014). A mouse knock-in mod el homozygous for the p.Glu292Val variant displayed phenotypes consistent with i nterstitial lung disease (Tomer 2013). This variant has been identified in 0.43% (543/126312) of European chromosomes, including 3 homozygotes, by the Genome Ag gregation Database (gnomAD, http://gnomad.broadinstitute.org/; dbSNP rs149989682 ) and is reported in ClinVar (Variation ID: 203381). Please note that for diseas es with recessive inheritance, pathogenic variants may be present at a low frequ ency in the general population. Computational prediction tools and conservation analysis suggest that the p.Glu292Val variant may impact the protein, though thi s information is not predictive enough to determine pathogenicity. In summary, a lthough additional studies are required to fully establish its clinical signific ance, the p.Glu292Val variant is likely pathogenic. ACMG/AMP Criteria applied: P M3_Very Strong; PS3; PP3; BS1_Supporting. -

Pulmonary valve insufficiency;C0035229:Respiratory insufficiency;C2973725:Pulmonary arterial hypertension Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Center for Personalized Medicine, Children's Hospital Los Angeles

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- -

Hereditary pulmonary alveolar proteinosis Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 01, 2022

The p.E292V pathogenic mutation (also known as c.875A>T), located in coding exon 6 of the ABCA3 gene, results from an A to T substitution at nucleotide position 875. The glutamic acid at codon 292 is replaced by valine, an amino acid with dissimilar properties. This is the most common ABCA3 mutation reported to date in pediatric interstitial lung disease and has a carrier rate of 1 in 275 individuals in the United States. In a study with 12 confirmed ABCA3 cases, this mutation was found in the compound heterozygous state in three individuals and in the homozygous state in one individual. Since the four affected individuals were all alive, p.E292V was speculated to be a mild mutation (Turcu S et al. Arch Dis Child. 2013;98(7):490-5). In another study with 185 individuals identified with ABCA3 mutations, this mutation was detected in 16 individuals. One homozygous infant presented with neonatal respiratory failure and died shortly after birth, while the remaining 15 compound heterozygous individuals had variable outcomes (Wambach JA et al. Am J Respir Crit Care Med. 2014;189(12):1538-43). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.70
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Pathogenic	0.44
Cadd	Pathogenic	31
Dann	Uncertain	0.99
DEOGEN2	Pathogenic	0.84	D;.
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.85	D;T
M_CAP	Pathogenic	0.82	D
MetaRNN	Benign	0.18	T;T
MetaSVM	Pathogenic	0.97	D
MutationAssessor	Pathogenic	3.7	H;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.45	T
PROVEAN	Pathogenic	-6.5	D;D
REVEL	Pathogenic	0.95
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0010	D;D
Polyphen		1.0	D;.
Vest4		0.93
MVP		0.97
MPC		0.92
ClinPred		0.90	D
GERP RS		5.0
Varity_R		0.91
gMVP		0.87

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.66
dbscSNV1_RF	Pathogenic	0.78
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs149989682; hg19: chr16-2367764; COSMIC: COSV100069309;