5-74721104-C-A
Variant summary
Our verdict is Benign. Variant got -10 ACMG points: 2P and 12B. PM2BP4_StrongBP6_Very_Strong
The NM_000521.4(HEXB):c.1614-14C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000275 in 1,585,130 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 Likely benign (★★).
Frequency
Consequence
NM_000521.4 intron
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: 0.000178 AC: 27AN: 152006Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000163 AC: 41AN: 250854Hom.: 0 AF XY: 0.000192 AC XY: 26AN XY: 135646
GnomAD4 exome AF: 0.000285 AC: 409AN: 1433006Hom.: 0 Cov.: 27 AF XY: 0.000278 AC XY: 199AN XY: 714914
GnomAD4 genome AF: 0.000177 AC: 27AN: 152124Hom.: 0 Cov.: 32 AF XY: 0.000161 AC XY: 12AN XY: 74384
ClinVar
Submissions by phenotype
not specified Benign:4
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Variant summary: HEXB c.1614-14C>A 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, which a functional study, Sobek_2012, supports these predictions. The variant allele was found at a frequency of 0.00017 in 277098 control chromosomes (gnomAD and publication). This frequency is not significantly higher than expected for a pathogenic variant in HEXB causing Sandhoff Disease (0.00017 vs 0.0015), allowing no conclusion about variant significance. c.1614-14C>A has been reported in the literature in individuals affected with Sandhoff Disease (Giagnard_2013, Jarnes_2017, Sobek_2012). Although multiple reported affected individuals carried the variant in cis with another pathogenic HEXB variant, in particular, the exon 1-5 deletion, c.-117_669del was reported to be linked with the variant (Sobek_2012). Two ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as likely benign. Based on the evidence outlined above, the variant was classified as benign. -
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. -
Sandhoff disease Benign:4
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
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not provided Benign:1
HEXB: BP2 -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at