rs758237894
Variant summary
Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS2
The NM_017617.5(NOTCH1):c.*7C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000439 in 1,595,578 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).
Frequency
Consequence
NM_017617.5 3_prime_UTR
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -10 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000394 AC: 6AN: 152212Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000317 AC: 7AN: 220830Hom.: 0 AF XY: 0.0000330 AC XY: 4AN XY: 121162
GnomAD4 exome AF: 0.0000443 AC: 64AN: 1443366Hom.: 0 Cov.: 31 AF XY: 0.0000376 AC XY: 27AN XY: 717258
GnomAD4 genome AF: 0.0000394 AC: 6AN: 152212Hom.: 0 Cov.: 33 AF XY: 0.0000538 AC XY: 4AN XY: 74358
ClinVar
Submissions by phenotype
not specified Benign:1
Variant summary: NOTCH1 c.*7C>T is located in the untranslated mRNA region downstream of the termination codon. 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 4.4e-05 in 1595578 control chromosomes (gnomAD database v4). The observed variant frequency is approximately 70 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.*7C>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: 3037250). Based on the evidence outlined above, the variant was classified as benign. -
NOTCH1-related disorder Benign:1
This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at