rs142977595
Positions:
Variant summary
Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS2
The NM_001089.3(ABCA3):āc.371A>Gā(p.Asn124Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00136 in 1,610,770 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: š 0.00082 ( 0 hom., cov: 31)
Exomes š: 0.0014 ( 4 hom. )
Consequence
ABCA3
NM_001089.3 missense
NM_001089.3 missense
Scores
1
4
14
Clinical Significance
Conservation
PhyloP100: 4.84
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 Benign. Variant got -7 ACMG points.
BP4
?
Computational evidence support a benign effect (MetaRNN=0.2047585).
BP6
?
Variant 16-2324480-T-C is Benign according to our data. Variant chr16-2324480-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 504721.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=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.371A>G | p.Asn124Ser | missense_variant | 6/33 | ENST00000301732.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ABCA3 | ENST00000301732.10 | c.371A>G | p.Asn124Ser | missense_variant | 6/33 | 1 | NM_001089.3 | P1 | |
ABCA3 | ENST00000382381.7 | c.371A>G | p.Asn124Ser | missense_variant | 6/32 | 1 | |||
ABCA3 | ENST00000567910.1 | c.371A>G | p.Asn124Ser | missense_variant | 5/6 | 1 | |||
ABCA3 | ENST00000563623.5 | n.934A>G | non_coding_transcript_exon_variant | 6/20 | 1 |
Frequencies
GnomAD3 genomes ? AF: 0.000823 AC: 125AN: 151906Hom.: 0 Cov.: 31
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GnomAD3 exomes AF: 0.00108 AC: 268AN: 248206Hom.: 1 AF XY: 0.00105 AC XY: 142AN XY: 134600
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GnomAD4 exome AF: 0.00141 AC: 2062AN: 1458746Hom.: 4 Cov.: 31 AF XY: 0.00143 AC XY: 1035AN XY: 725674
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GnomAD4 genome ? AF: 0.000822 AC: 125AN: 152024Hom.: 0 Cov.: 31 AF XY: 0.000740 AC XY: 55AN XY: 74300
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:2
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Interstitial lung disease due to ABCA3 deficiency Uncertain:1
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. - |
Hereditary pulmonary alveolar proteinosis Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 26, 2018 | The p.N124S variant (also known as c.371A>G), located in coding exon 3 of the ABCA3 gene, results from an A to G substitution at nucleotide position 371. The asparagine at codon 124 is replaced by serine, an amino acid with highly similar properties. A study of the N-linked glycosylation site at residue 124 found that single mutations at the glycosylation site fail to disrupt the trafficking pattern of ABCA3 to cytosolic lysosomal-related organelles or alter their function as lipid transporters (Beers MF et al. Am. J. Physiol. Lung Cell Mol. Physiol., 2013 Dec;305:L970-80). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on available evidence to date, the clinical significance of this alteration remains unclear. - |
not specified Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jan 22, 2019 | The p.Asn124Ser variant in ABCA3 is classified as likely benign because it has has been identified in 0.16% (209/128312) of European and 0.13% (32/23120) of Finnish chromosomes including 1 homozygote by gnomAD (http://gnomad.broadinstitute.org), and because computational prediction tools and conservation analysis suggest that the variant may not impact the protein. ACMG/AMP criteria applied: BS1_Supporting, BP4. - |
not provided Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 28, 2024 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
DEOGEN2
Benign
T;.;.
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D;D
M_CAP
Pathogenic
D
MetaRNN
Benign
T;T;T
MetaSVM
Uncertain
D
MutationAssessor
Benign
L;.;L
MutationTaster
Benign
D;D;D
PrimateAI
Benign
T
PROVEAN
Benign
N;N;N
REVEL
Uncertain
Sift
Benign
T;T;T
Sift4G
Benign
T;T;T
Polyphen
B;.;.
Vest4
MVP
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at