19-15187216-T-C
Variant summary
Our verdict is Likely benign. The variant received -1 ACMG points: 2P and 3B. PM1BP4_ModerateBP6
The NM_000435.3(NOTCH3):c.1729A>G(p.Thr577Ala) 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 1,613,988 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_000435.3 missense
Scores
Clinical Significance
Conservation
Publications
- cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1Inheritance: AR, AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Genomics England PanelApp, Laboratory for Molecular Medicine, Orphanet, Labcorp Genetics (formerly Invitae)
- lateral meningocele syndromeInheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)
- infantile myofibromatosisInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- myofibromatosis, infantile, 2Inheritance: AD Classification: LIMITED Submitted by: G2P
- pulmonary arterial hypertensionInheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
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ACMG classification
Our verdict: Likely_benign. The variant received -1 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
NOTCH3 | ENST00000263388.7 | c.1729A>G | p.Thr577Ala | missense_variant | Exon 11 of 33 | 1 | NM_000435.3 | ENSP00000263388.1 | ||
NOTCH3 | ENST00000601011.1 | c.1726A>G | p.Thr576Ala | missense_variant | Exon 11 of 23 | 5 | ENSP00000473138.1 |
Frequencies
GnomAD3 genomes AF: 0.0000328 AC: 5AN: 152222Hom.: 0 Cov.: 33 show subpopulations
GnomAD2 exomes AF: 0.0000239 AC: 6AN: 250702 AF XY: 0.0000147 show subpopulations
GnomAD4 exome AF: 0.0000260 AC: 38AN: 1461766Hom.: 0 Cov.: 33 AF XY: 0.0000344 AC XY: 25AN XY: 727196 show subpopulations
Age Distribution
GnomAD4 genome AF: 0.0000328 AC: 5AN: 152222Hom.: 0 Cov.: 33 AF XY: 0.0000403 AC XY: 3AN XY: 74372 show subpopulations
Age Distribution
ClinVar
Submissions by phenotype
not provided Uncertain:1Benign:1
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The NOTCH3 c.1729A>G; p.Thr577Ala variant (rs368181126; ClinVar ID: 447797) is reported in the literature in an individual affected with CADASIL, although supporting evidence of pathogenicity was not provided (Ferreira 2007). This variant is found in the general population with an overall allele frequency of 0.002% (7/282,084 alleles) in the Genome Aggregation Database (v2.1.1). Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.481). Most pathogenic NOTCH3 variants occur in exons 2-24 and either create or destroy a cysteine residue within an EGF-like domain (Rutten 2014). However, there are several amino acid substitutions not involving cysteine that may be disease-associated (Muino 2017). Although the p.Thr577Ala variant does not involve a cysteine residue, due to its low population frequency its clinical significance is uncertain. References: Ferreira S et al. Novel human pathological mutations. Gene symbol: NOTCH3. Disease: cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. Hum Genet. 2007 Jun;121(5):651-2. PMID: 17879453. Muino E et al. Systematic Review of Cysteine-Sparing NOTCH3 Missense Mutations in Patients with Clinical Suspicion of CADASIL. Int J Mol Sci. 2017 Sep 13;18(9). pii: E1964. PMID: 28902129. Rutten JW et al. Interpretation of NOTCH3 mutations in the diagnosis of CADASIL. Expert Rev Mol Diagn. 2014 Jun;14(5):593-603. PMID: 24844136. -
not specified Uncertain:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at