chr16-2297467-G-A
Variant summary
Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2
The NM_001089.3(ABCA3):c.2125C>T(p.Arg709Trp) variant causes a missense change. The variant allele was found at a frequency of 0.00221 in 1,613,790 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R709Q) has been classified as Likely benign.
Frequency
Consequence
NM_001089.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -9 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ABCA3 | NM_001089.3 | c.2125C>T | p.Arg709Trp | missense_variant | 17/33 | ENST00000301732.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ABCA3 | ENST00000301732.10 | c.2125C>T | p.Arg709Trp | missense_variant | 17/33 | 1 | NM_001089.3 | P1 | |
ABCA3 | ENST00000382381.7 | c.1951C>T | p.Arg651Trp | missense_variant | 16/32 | 1 | |||
ABCA3 | ENST00000563623.5 | n.2688C>T | non_coding_transcript_exon_variant | 17/20 | 1 |
Frequencies
GnomAD3 genomes AF: 0.00162 AC: 247AN: 152142Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00130 AC: 327AN: 251336Hom.: 0 AF XY: 0.00119 AC XY: 162AN XY: 135878
GnomAD4 exome AF: 0.00227 AC: 3321AN: 1461530Hom.: 7 Cov.: 32 AF XY: 0.00217 AC XY: 1581AN XY: 727070
GnomAD4 genome AF: 0.00162 AC: 247AN: 152260Hom.: 0 Cov.: 32 AF XY: 0.00138 AC XY: 103AN XY: 74448
ClinVar
Submissions by phenotype
Interstitial lung disease due to ABCA3 deficiency Uncertain:1Benign:1
Likely benign, 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). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Johns Hopkins Genomics, Johns Hopkins University | Jun 04, 2021 | - - |
not provided Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | May 18, 2022 | 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: 22068586, 27516224, 33224783, 32238781, 34638622) - |
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 31, 2024 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jun 21, 2016 | Variant classified as Uncertain Significance - Favor Benign. The p.Arg709Trp var iant in ABCA3 has been reported in the heterozygous state in 1 child with neonat al respiratory distress (NRD)(Flamein 2012). This variant has also been identifi ed by our laboratory in 1 neonate with pulmonary hypertension, pulmonary valve d ysplasia, left aortic arch with aberrant right subclavian artery, cardiomyopathy (RV dilation, mild LVH), and hypotonia. It has been identified in 0.2% (24/1036 4) of African chromosomes by the Exome Aggregation Consortium (ExAC, http://exac .broadinstitute.org; dbSNP rs148671332). Computational prediction tools and cons ervation analysis suggest that this variant may not impact the protein, though t his information is not predictive enough to rule out pathogenicity. In summary, while the clinical significance of the p.Arg709Trp variant is uncertain, its fre quency suggests that it is more likely to be benign. - |
ABCA3-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Mar 10, 2023 | The ABCA3 c.2125C>T variant is predicted to result in the amino acid substitution p.Arg709Trp. This variant has been reported in individuals with ABCA3-related disease (Flamein et al. 2012. PubMed ID: 22068586; Kröner et al. 2016. PubMed ID: 27516224; Sallmon et al. 2020. PubMed ID: 33224783). However, in one individual a second variant was not identified (Flamein et al. 2012. PubMed ID: 22068586). This variant is reported in 0.21% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/16-2347468-G-A). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
Hereditary pulmonary alveolar proteinosis Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 14, 2019 | The p.R709W variant (also known as c.2125C>T), located in coding exon 14 of the ABCA3 gene, results from a C to T substitution at nucleotide position 2125. The arginine at codon 709 is replaced by tryptophan, an amino acid with dissimilar properties. This variant was detected in an individual with interstitial lung disease; a second ABCA3 alteration was not detected (Flamein F et al. Hum. Mol. Genet., 2012 Feb;21:765-75). In addition, this variant was detected in a adult individual with dyspnea withe exercise and pulmonary alveolar proteinosis; a second ABCA3 alteration was detected, but the phase is unknown (Kröner C et al. Thorax, 2017 Mar;72:213-220). This amino acid position is poorly 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 variant remains unclear. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at