16-2317763-T-A
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Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PP3PP5BP4
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
NM_001089.3 missense, splice_region
Scores
13
2
4
Splicing: ADA: 0.6552
1
1
Clinical Significance
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]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 1 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: {Likely_pathogenic=8, Uncertain_significance=1, Pathogenic=8}. 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.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| ABCA3 | NM_001089.3 | c.875A>T | p.Glu292Val | missense_variant, splice_region_variant | 9/33 | ENST00000301732.10 | NP_001080.2 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| ABCA3 | ENST00000301732.10 | c.875A>T | p.Glu292Val | missense_variant, splice_region_variant | 9/33 | 1 | NM_001089.3 | ENSP00000301732 | P1 | |
| ABCA3 | ENST00000382381.7 | c.875A>T | p.Glu292Val | missense_variant, splice_region_variant | 9/32 | 1 | ENSP00000371818 | |||
| ABCA3 | ENST00000563623.5 | n.1438A>T | splice_region_variant, non_coding_transcript_exon_variant | 9/20 | 1 |
Frequencies
GnomAD3 genomes 0.00298 AC: 454AN: 152240Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00229 AC: 576AN: 250982Hom.: 3 AF XY: 0.00238 AC XY: 323AN XY: 135680
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GnomAD4 exome AF: 0.00469 AC: 6862AN: 1461576Hom.: 20 Cov.: 32 AF XY: 0.00457 AC XY: 3324AN XY: 727100
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GnomAD4 genome 0.00298 AC: 454AN: 152358Hom.: 0 Cov.: 32 AF XY: 0.00286 AC XY: 213AN XY: 74500
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:19Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link
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. - |
| 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 | 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 | Clinical Genomics Laboratory, 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]. - |
| 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 | Aug 01, 2024 | 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. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0023 in 250982 control chromosomes, 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). 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). The following publications have been ascertained in the context of this evaluation (PMID: 23625987, 29566461, 15976379, 22434821, 18676873, 34132118, 27374344, 32692933). ClinVar contains an entry for this variant (Variation ID: 203381). Based on the evidence outlined above, the variant was classified as likely pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Mendelics | May 04, 2022 | - - |
| 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, no assertion criteria provided | clinical testing | Seattle Children's Hospital Molecular Genetics Laboratory, Seattle Children's Hospital | - | - - |
not provided Pathogenic:5Uncertain:1
| Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Sep 12, 2016 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Feb 07, 2024 | Variant found to be over-represented in newborns with respiratory distress syndrome suggesting that E292V or its haplotype impart increased genetic risk for RDS (PMID: 18317237); Published functional studies demonstrate that the variant contributes to loss of epithelial cell differentiation (PMID: 22434821); 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, 25073622, 18676873, 24136335, 18603241, 22866751, 27516224, 23166334, 30609409, 25553246, 28034695, 27374344, 29505158, 22800827, 22145626, 18246475, 29569581, 29255193, 22304854, 29566461, 31980526, 32238781, 31589614, 34426522, 34132118, 33526094, 32692933, 32196812, 33359301, 33708521, 23625987, 34662886, 30755392, 18317237, 15976379, 24871971, 22434821) - |
| 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 | Labcorp Genetics (formerly Invitae), Labcorp | 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. - |
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. - |
Interstitial lung disease 2 Pathogenic:1
| Likely pathogenic, criteria provided, single submitter | research | Alder lab, University of Pittsburgh | Aug 01, 2022 | - - |
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 | - | - - |
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
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Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Pathogenic
D;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Benign
D;T
M_CAP
Pathogenic
D
MetaRNN
Benign
T;T
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
H;.
MutationTaster
Benign
D;D
PrimateAI
Benign
T
PROVEAN
Pathogenic
D;D
REVEL
Pathogenic
Sift
Pathogenic
D;D
Sift4G
Pathogenic
D;D
Polyphen
D;.
Vest4
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at