chr16-2326201-C-T
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong
The NM_001089.3(ABCA3):c.128G>A(p.Arg43His) variant causes a missense change. The variant allele was found at a frequency of 0.0000198 in 1,613,970 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_001089.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
ABCA3 | ENST00000301732.10 | c.128G>A | p.Arg43His | missense_variant | Exon 5 of 33 | 1 | NM_001089.3 | ENSP00000301732.5 | ||
ABCA3 | ENST00000382381.7 | c.128G>A | p.Arg43His | missense_variant | Exon 5 of 32 | 1 | ENSP00000371818.3 | |||
ABCA3 | ENST00000567910.1 | c.128G>A | p.Arg43His | missense_variant | Exon 4 of 6 | 1 | ENSP00000454397.1 | |||
ABCA3 | ENST00000563623.5 | n.691G>A | non_coding_transcript_exon_variant | Exon 5 of 20 | 1 |
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152176Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000159 AC: 4AN: 251334Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135846
GnomAD4 exome AF: 0.0000198 AC: 29AN: 1461794Hom.: 0 Cov.: 35 AF XY: 0.0000234 AC XY: 17AN XY: 727186
GnomAD4 genome AF: 0.0000197 AC: 3AN: 152176Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74332
ClinVar
Submissions by phenotype
Interstitial lung disease due to ABCA3 deficiency Pathogenic:2
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Primary interstitial lung disease specific to childhood due to pulmonary surfactant protein anomalies Pathogenic:1
The p.Arg43His variant in ABCA3 has been previously reported in 1 homozygous inf ant with interstitial lung disease (ILD) and in 3 compound heterozygous infants/ children with ILD (Doan 2008, Agrawal 2012, Wambach 2014). In addition, two othe r variants at this codon (p.Arg43Leu and p.Arg43Cys) have each been reported in 2 compound heterozygous children with ILD and one of these variants (p.Arg43Cys) segregated with disease in an affected relative, suggesting that changes to thi s residue are not tolerated (Brasch 2006, Garmany 2006, Agrawal 2012, Wambach 20 14). The p.Arg43His variant has been identified in 1/66674 European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org). Alth ough this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. Computational predic tion tools and conservation analysis do not provide strong support for or agains t an impact the protein. In summary, this variant meets our criteria to be class ified as pathogenic for ILD in an autosomal recessive manner(http://www.partners .org/personalizedmedicine/LMM). -
not provided Pathogenic:1
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 43 of the ABCA3 protein (p.Arg43His). This variant is present in population databases (rs754714105, gnomAD 0.01%). This missense change has been observed in individuals with autosomal recessive childhood interstitial lung disease (PMID: 18024538, 24871971). ClinVar contains an entry for this variant (Variation ID: 228321). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ABCA3 protein function. This variant disrupts the p.Arg43 amino acid residue in ABCA3. Other variant(s) that disrupt this residue have been observed in individuals with ABCA3-related conditions (PMID: 22337229, 24871971), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -
Hereditary pulmonary alveolar proteinosis Pathogenic:1
The p.R43H pathogenic mutation (also known as c.128G>A), located in coding exon 2 of the ABCA3 gene, results from a G to A substitution at nucleotide position 128. The arginine at codon 43 is replaced by histidine, an amino acid with highly similar properties. This alteration has been detected in the homozygous state or in conjunction with other ABCA3 disease-causing variants in multiple individuals with ABCA3-related surfactant dysfunction (Doan ML et al. Thorax, 2008 Apr;63:366-73; Agrawal A et al. Pediatr Res, 2012 Jun;71:633-7; Wambach JA et al. Am J Respir Crit Care Med, 2014 Jun;189:1538-43; Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at