rs544773641
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM1BS2_Supporting
The NM_000435.3(NOTCH3):c.472G>A(p.Asp158Asn) variant causes a missense change. The variant allele was found at a frequency of 0.0000217 in 1,612,708 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_000435.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 1 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000526 AC: 8AN: 152074Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000365 AC: 9AN: 246260Hom.: 0 AF XY: 0.0000372 AC XY: 5AN XY: 134334
GnomAD4 exome AF: 0.0000185 AC: 27AN: 1460516Hom.: 0 Cov.: 40 AF XY: 0.0000220 AC XY: 16AN XY: 726610
GnomAD4 genome AF: 0.0000526 AC: 8AN: 152192Hom.: 0 Cov.: 32 AF XY: 0.0000806 AC XY: 6AN XY: 74412
ClinVar
Submissions by phenotype
Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1 Uncertain:1
Criteria applied: PS4_SUP,PM2_SUP,PP2,PP3 -
not provided Uncertain:1
This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 158 of the NOTCH3 protein (p.Asp158Asn). This variant is present in population databases (rs544773641, gnomAD 0.02%). This missense change has been observed in individual(s) with clinical features of cerebral arteriopathy with subcortical infarcts and leukoencephalopathy (PMID: 30076350). ClinVar contains an entry for this variant (Variation ID: 447851). 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 NOTCH3 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
not specified Benign:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at