11-64807686-G-T
Variant summary
Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2
The NM_001370259.2(MEN1):c.655-6C>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000199 in 1,614,102 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_001370259.2 splice_region, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -9 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
MEN1 | NM_001370259.2 | c.655-6C>A | splice_region_variant, intron_variant | Intron 3 of 9 | ENST00000450708.7 | NP_001357188.2 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000920 AC: 14AN: 152190Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000144 AC: 36AN: 250756Hom.: 0 AF XY: 0.000140 AC XY: 19AN XY: 135584
GnomAD4 exome AF: 0.000211 AC: 308AN: 1461794Hom.: 0 Cov.: 33 AF XY: 0.000194 AC XY: 141AN XY: 727188
GnomAD4 genome AF: 0.0000919 AC: 14AN: 152308Hom.: 0 Cov.: 32 AF XY: 0.0000940 AC XY: 7AN XY: 74490
ClinVar
Submissions by phenotype
Multiple endocrine neoplasia, type 1 Benign:3
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This variant is considered likely benign. This variant is intronic and is not expected to impact mRNA splicing. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance. -
not provided Uncertain:2
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This variant is denoted MEN1 c.655-6C>A or IVS3-6C>A and consists of a C>A nucleotide substitution at the -6 position of intron 3 of the MEN1 gene. Multiple in silico models predict this variant to destroy the nearby natural splice acceptor site and to possibly cause abnormal gene splicing. However, in the absence of RNA or functional studies, the actual effect of this variant is unknown.? This variant has been observed in at least one kindred with a diagnosis or features of Multiple Endocrine Neoplasia type 1 (J?ger 2006). MEN1 c.655-6C>A was observed at an allele frequency of 0.02% (8/34,394) in individuals of Latino ancestry in large population cohorts (Lek 2016).The cytosine (C) nucleotide that is altered is not conserved. Based on currently available evidence, it is unclear whether MEN1 c.655-6C>A is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. -
not specified Uncertain:1
Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Intronic, reported in 1 proband. -
Hereditary cancer-predisposing syndrome Benign:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at