rs45592239

Positions:

• chr16-2295708-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_001089.3(ABCA3):​c.2296C>T​(p.Pro766Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00214 in 1,614,026 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. P766P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0017 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0022 (4 hom.)
• Consequence: ABCA3 NM_001089.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:2
• Conservation: PhyloP100: 3.56

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 Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010553002).
• BP6: Variant 16-2295708-G-A is Benign according to our data. Variant chr16-2295708-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 178696.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=5, Likely_benign=2}.
• BS2: High Homozygotes in GnomAdExome4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ABCA3	NM_001089.3	c.2296C>T	p.Pro766Ser	missense_variant	18/33	ENST00000301732.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ABCA3	ENST00000301732.10	c.2296C>T	p.Pro766Ser	missense_variant	18/33	1	NM_001089.3	P1
ABCA3	ENST00000382381.7	c.2122C>T	p.Pro708Ser	missense_variant	17/32	1
ABCA3	ENST00000563623.5	n.2859C>T		non_coding_transcript_exon_variant	18/20	1

Frequencies

GnomAD3 genomes AF: 0.00167 AC: 255 AN: 152240 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000458

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00329

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00171 AC: 429 AN: 251166 Hom.: 0 AF XY: 0.00179 AC XY: 243 AN XY: 135802

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.000202

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000784

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.00338

Gnomad OTH exome AF: 0.00130

GnomAD4 exome AF: 0.00218 AC: 3193 AN: 1461668 Hom.: 4 Cov.: 32 AF XY: 0.00208 AC XY: 1515 AN XY: 727140

Gnomad4 AFR exome AF: 0.000209

Gnomad4 AMR exome AF: 0.000179

Gnomad4 ASJ exome AF: 0.000115

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000951

Gnomad4 FIN exome AF: 0.000320

Gnomad4 NFE exome AF: 0.00266

Gnomad4 OTH exome AF: 0.00192

GnomAD4 genome AF: 0.00169 AC: 258 AN: 152358 Hom.: 1 Cov.: 32 AF XY: 0.00140 AC XY: 104 AN XY: 74512

Gnomad4 AFR AF: 0.000457

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00186

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.00329

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00264 Hom.: 3

Bravo AF: 0.00152

TwinsUK AF: 0.00297 AC: 11

ALSPAC AF: 0.00234 AC: 9

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00256 AC: 22

ExAC AF: 0.00192 AC: 233

Asia WGS AF: 0.000289 AC: 2 AN: 3478

EpiCase AF: 0.00240

EpiControl AF: 0.00261

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Interstitial lung disease due to ABCA3 deficiency Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	Oct 28, 2019	This ABCA3 variant has been reported in the heterozygous state and as part of a complex allele with p.Leu960Phe. This patient does not carry the latter variant and the clinical significance of p.Pro766Ser alone is unclear. There are conflicting interpretations of the pathogenicity of this variant in ClinVar. One submitter classified it as a variant of uncertain clinical significance and one as likely benign. Of three bioinformatics tools queried, two predict that the substitution would be damaging, while one predicts that it would be tolerated. The proline residue at this position is highly evolutionarily conserved across most higher order species. Due to insufficient evidence, we consider the clinical significance of c.2296C>T to be uncertain at this time. -

not specified Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 14, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 05, 2014	Variant classified as Uncertain Significance - Favor Benign. The p.Pro766Ser var iant in ABCA3 has been reported in at least 10 individuals with various pulmonar y phenotypes (Baekvad-Hansen 2012). In addition, this variant has been identifie d in 0.26% (22/8600) of European American chromosomes by the NHLBI Exome Sequenc ing Project (http://evs.gs.washington.edu/EVS/; dbSNP rs45592239). Computational prediction tools and conservation analysis suggest that the p.Pro766Ser variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In fact, 2 fish species (southern platyfish and spotted gar) carry a serine (Ser) at this position, suggesting that this change may be tolerated. In summary, while the clinical significance of the p.Pro766Ser varian t is uncertain, its frequency and the presence of the variant amino acid in othe r species suggests that it is more likely to be benign. -

not provided Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	May 18, 2022	Observed in the homozygous state in three unrelated patients with interstitial lung disease and in the compound heterozygous state with a frameshift variant in another patient with interstitial lung disease (Wambach et al., 2014); in all cases P766S was observed in cis with L960F; Observed in the heterozygous state in four individuals with variable pulmnoary phenotypes including asthma, COPD, and interstitial lung disease and in 121 patients from a general population health study (Copenhagen City Heart study) without a significant pulmonary phenotype, including one individual who was compound heterozygous for P766S and another missense variant (Baekvad-Hansen et al., 2012); Identified in the compound heterozygous state along with a frameshift variant in an infant with interstitial lung disease (Garmany et al., 2006); P766S was in cis with L960F in this individual; Identified in the heterozygous state along with L960F and another missense variant in a patient with interstitial lung disease (Turcu et al., 2013); the phase of these variants was not determined; 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: 24871971, 22866751, 16641205, 23625987, 27535533, 34638622, 35170262) -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 30, 2024	- -

Hereditary pulmonary alveolar proteinosis Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 25, 2021

The p.P766S variant (also known as c.2296C>T), located in coding exon 15 of the ABCA3 gene, results from a C to T substitution at nucleotide position 2296. The proline at codon 766 is replaced by serine, an amino acid with similar properties. This variant was identified in cis with p.L960F and in trans with a frameshift alteration in an infant with progressive lung disease and a histopathologic diagnosis of pulmonary alveolar proteinosis (Garmany TH et al. Pediatr. Res., 2006 Jun;59:801-5). In another study, the complex allele, p.[P766S; L960F], was identified in four individuals with severe pulmonary symptoms and a third ABCA3 alteration in trans (Wambach JA et al. Am. J. Respir. Crit. Care Med., 2014 Jun;189:1538-43). The p.P766S variant was identified in conjunction with two additional ABCA3 alterations in an individual with interstitial lung disease and chronic interstitial pneumonitis diagnosed at one year of age and a history of respiratory distress syndrome at birth; however, the phase of the alterations was not provided (Turcu S et al. Arch. Dis. Child., 2013 Jul;98:490-5).This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on available evidence to date, the clinical significance of this variant remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.68	D;.
Eigen	Benign	-0.066
Eigen_PC	Benign	0.091
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.87	D;D
M_CAP	Benign	0.029	D
MetaRNN	Benign	0.011	T;T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	1.1	L;.
MutationTaster	Benign	0.99	D;D
PrimateAI	Benign	0.36	T
PROVEAN	Pathogenic	-5.6	D;D
REVEL	Benign	0.11
Sift	Benign	0.041	D;D
Sift4G	Benign	0.19	T;T
Polyphen		0.22	B;.
Vest4		0.30
MVP		0.71
MPC		0.27
ClinPred		0.044	T
GERP RS		4.7
Varity_R		0.25
gMVP		0.76

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs45592239; hg19: chr16-2345709;