rs375025242
Variant summary
Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2
The NM_017617.5(NOTCH1):c.7400C>T(p.Ser2467Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000148 in 1,593,036 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 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_017617.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -9 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000105 AC: 16AN: 152198Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000125 AC: 27AN: 215786Hom.: 0 AF XY: 0.000144 AC XY: 17AN XY: 117734
GnomAD4 exome AF: 0.000152 AC: 219AN: 1440838Hom.: 0 Cov.: 31 AF XY: 0.000148 AC XY: 106AN XY: 714664
GnomAD4 genome AF: 0.000105 AC: 16AN: 152198Hom.: 0 Cov.: 33 AF XY: 0.000148 AC XY: 11AN XY: 74352
ClinVar
Submissions by phenotype
Familial thoracic aortic aneurysm and aortic dissection Uncertain:1Benign:1
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not specified Benign:1Other:1
Variant summary: NOTCH1 c.7400C>T (p.Ser2467Leu) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00013 in 215786 control chromosomes. The observed variant frequency is approximately 200.2 fold of the estimated maximal expected allele frequency for a pathogenic variant in NOTCH1 causing Adams-Oliver Syndrome 5 phenotype (6.3e-07). To our knowledge, no occurrence of c.7400C>T in individuals affected with Adams-Oliver Syndrome 5 and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 134947). Based on the evidence outlined above, the variant was classified as likely benign. -
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not provided Uncertain:1
Has not been previously reported in association with TAAD to our knowledge; In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 30341550, 24728327) -
Adams-Oliver syndrome 5 Benign:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at