rs199786076
Variant summary
Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2
The NM_017617.5(NOTCH1):c.6083-5C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000576 in 1,613,244 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Consequence
NM_017617.5 splice_region, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -16 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000854 AC: 13AN: 152260Hom.: 0 Cov.: 34
GnomAD3 exomes AF: 0.0000723 AC: 18AN: 248892Hom.: 0 AF XY: 0.0000887 AC XY: 12AN XY: 135222
GnomAD4 exome AF: 0.0000548 AC: 80AN: 1460866Hom.: 0 Cov.: 32 AF XY: 0.0000592 AC XY: 43AN XY: 726758
GnomAD4 genome AF: 0.0000853 AC: 13AN: 152378Hom.: 0 Cov.: 34 AF XY: 0.0000537 AC XY: 4AN XY: 74510
ClinVar
Submissions by phenotype
Adams-Oliver syndrome 5 Benign:2
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not specified Benign:1
Variant summary: NOTCH1 c.6083-5C>T alters a nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 7.2e-05 in 248892 control chromosomes, predominantly at a frequency of 0.00011 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 176 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.6083-5C>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: 415418). Based on the evidence outlined above, the variant was classified as benign. -
not provided Benign:1
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Aortic valve disease 1 Benign:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at