16-2295663-C-T
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The NM_001089.3(ABCA3):c.2341G>A(p.Val781Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000266 in 1,613,928 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Consequence
NM_001089.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 2 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
ABCA3 | ENST00000301732.10 | c.2341G>A | p.Val781Met | missense_variant | Exon 18 of 33 | 1 | NM_001089.3 | ENSP00000301732.5 | ||
ABCA3 | ENST00000382381.7 | c.2167G>A | p.Val723Met | missense_variant | Exon 17 of 32 | 1 | ENSP00000371818.3 | |||
ABCA3 | ENST00000563623.5 | n.2904G>A | non_coding_transcript_exon_variant | Exon 18 of 20 | 1 |
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152238Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000199 AC: 5AN: 251164Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135792
GnomAD4 exome AF: 0.0000274 AC: 40AN: 1461690Hom.: 0 Cov.: 32 AF XY: 0.0000220 AC XY: 16AN XY: 727166
GnomAD4 genome AF: 0.0000197 AC: 3AN: 152238Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74382
ClinVar
Submissions by phenotype
Interstitial lung disease due to ABCA3 deficiency Uncertain:2
This ABCA3 variant (rs771821923) is rare in large population datasets (gnomAD: 5/251164 total alleles; 0.002%; no homozygotes). This variant has not been reported in the literature, to our knowledge. A single submitter in ClinVar classifies this as a variant of uncertain clinical significance (Variation ID: 318487). Of two bioinformatics tools queried, one predicts that the substitution would be possibly damaging, while the second predicts that it would be damaging. The valine residue at this position is not highly evolutionarily conserved across the species assessed. Bioinformatic analysis predicts that this variant would not affect normal exon 18 splicing, although this has not been confirmed experimentally to our knowledge. The clinical significance of c.2341G>A is uncertain at this time. -
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Hereditary pulmonary alveolar proteinosis Uncertain:1
The c.2341G>A (p.V781M) alteration is located in exon 18 (coding exon 15) of the ABCA3 gene. This alteration results from a G to A substitution at nucleotide position 2341, causing the valine (V) at amino acid position 781 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at