rs63750146
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PP3_StrongPP5_Very_Strong
The NM_001171.6(ABCC6):c.3415G>A(p.Ala1139Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000285 in 1,613,774 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A1139V) has been classified as Uncertain significance.
Frequency
Consequence
NM_001171.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ABCC6 | NM_001171.6 | c.3415G>A | p.Ala1139Thr | missense_variant | 24/31 | ENST00000205557.12 | |
ABCC6 | NM_001351800.1 | c.3073G>A | p.Ala1025Thr | missense_variant | 24/31 | ||
ABCC6 | NR_147784.1 | n.3169-1520G>A | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ABCC6 | ENST00000205557.12 | c.3415G>A | p.Ala1139Thr | missense_variant | 24/31 | 1 | NM_001171.6 | P1 | |
ABCC6 | ENST00000622290.5 | c.3415G>A | p.Ala1139Thr | missense_variant, NMD_transcript_variant | 24/32 | 5 | |||
ABCC6 | ENST00000456970.6 | c.*516-1520G>A | intron_variant, NMD_transcript_variant | 2 |
Frequencies
GnomAD3 genomes AF: 0.0000329 AC: 5AN: 152192Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000517 AC: 13AN: 251274Hom.: 0 AF XY: 0.0000662 AC XY: 9AN XY: 135854
GnomAD4 exome AF: 0.0000281 AC: 41AN: 1461582Hom.: 0 Cov.: 33 AF XY: 0.0000316 AC XY: 23AN XY: 727074
GnomAD4 genome AF: 0.0000329 AC: 5AN: 152192Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4AN XY: 74350
ClinVar
Submissions by phenotype
not provided Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 15, 2024 | This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1139 of the ABCC6 protein (p.Ala1139Thr). This variant is present in population databases (rs63750146, gnomAD 0.08%). This missense change has been observed in individuals with pseudoxanthoma elasticum (PMID: 17617515, 34906475). ClinVar contains an entry for this variant (Variation ID: 381636). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on ABCC6 protein function. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Sep 29, 2016 | The A1139T variant in the ABCC6 gene also has been previously reported in patients with PXE, one of whom was homozygous for this variant (Pfendner et al., 2007). A1139T was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. It is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position within the topological cytoplasmic (IC8) domain that is conserved across species and in silico analysis predicts this variant is probably damaging to the protein structure/function. Missense variants in nearby residues (R1138W/P/Q) have been reported in the Human Gene Mutation Database in association with PXE (Stenson et al., 2014), supporting the functional importance of this region of the protein. - |
Autosomal recessive inherited pseudoxanthoma elasticum Pathogenic:1
Likely pathogenic, criteria provided, single submitter | research | PXE International | Mar 01, 2021 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at