rs9890283
Variant summary
Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2
The NM_001042492.3(NF1):c.3496+19T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00118 in 1,613,898 control chromosomes in the GnomAD database, including 24 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Consequence
NM_001042492.3 intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -20 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00625 AC: 950AN: 152046Hom.: 10 Cov.: 31
GnomAD3 exomes AF: 0.00169 AC: 425AN: 250870Hom.: 2 AF XY: 0.00110 AC XY: 149AN XY: 135606
GnomAD4 exome AF: 0.000651 AC: 951AN: 1461734Hom.: 14 Cov.: 32 AF XY: 0.000518 AC XY: 377AN XY: 727172
GnomAD4 genome AF: 0.00624 AC: 950AN: 152164Hom.: 10 Cov.: 31 AF XY: 0.00589 AC XY: 438AN XY: 74400
ClinVar
Submissions by phenotype
Neurofibromatosis, type 1 Benign:4
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not specified Benign:2
Variant summary: NF1 c.3496+19T>C alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 5/5 computational 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 0.0017 in 250870 control chromosomes in the gnomAD database, including 2 homozygotes. The observed variant frequency is approximately 677.6 fold the estimated maximal expected allele frequency for a pathogenic variant in NF1 causing Noonan Syndrome and Related Conditions phenotype (2.5e-06), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.3496+19T>C in individuals affected with Noonan Syndrome and Related Conditions and no experimental evidence demonstrating an impact on protein function have been reported. Two other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Both laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign. -
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not provided Benign:2
This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at