rs751281707
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Variant summary
Our verdict is Likely benign. Variant got -6 ACMG points: 4P and 10B. PVS1_StrongBP6_ModerateBA1
The NM_001388492.1(HTT):c.99_100delGC(p.Gln34fs) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0271 in 1,467,808 control chromosomes in the GnomAD database, including 1,250 homozygotes. Variant has been reported in ClinVar as Benign (★).
Frequency
Genomes: 𝑓 0.083 ( 669 hom., cov: 29)
Exomes 𝑓: 0.021 ( 581 hom. )
Consequence
HTT
NM_001388492.1 frameshift
NM_001388492.1 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 1.91
Genes affected
HTT (HGNC:4851): (huntingtin) Huntingtin is a disease gene linked to Huntington's disease, a neurodegenerative disorder characterized by loss of striatal neurons. This is thought to be caused by an expanded, unstable trinucleotide repeat in the huntingtin gene, which translates as a polyglutamine repeat in the protein product. A fairly broad range of trinucleotide repeats (9-35) has been identified in normal controls, and repeat numbers in excess of 40 have been described as pathological. The huntingtin locus is large, spanning 180 kb and consisting of 67 exons. The huntingtin gene is widely expressed and is required for normal development. It is expressed as 2 alternatively polyadenylated forms displaying different relative abundance in various fetal and adult tissues. The larger transcript is approximately 13.7 kb and is expressed predominantly in adult and fetal brain whereas the smaller transcript of approximately 10.3 kb is more widely expressed. The genetic defect leading to Huntington's disease may not necessarily eliminate transcription, but may confer a new property on the mRNA or alter the function of the protein. One candidate is the huntingtin-associated protein-1, highly expressed in brain, which has increased affinity for huntingtin protein with expanded polyglutamine repeats. This gene contains an upstream open reading frame in the 5' UTR that inhibits expression of the huntingtin gene product through translational repression. [provided by RefSeq, Jul 2016]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -6 ACMG points.
PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.99 CDS is truncated, and there are 1 pathogenic variants in the truncated region.
BP6
Variant 4-3074923-AGC-A is Benign according to our data. Variant chr4-3074923-AGC-A is described in ClinVar as [Benign]. Clinvar id is 402952.Status of the report is criteria_provided_single_submitter, 1 stars.
BA1
GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.155 is higher than 0.05.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
HTT | NM_001388492.1 | c.99_100delGC | p.Gln34fs | frameshift_variant | 1/67 | ENST00000355072.11 | NP_001375421.1 | |
HTT | NM_002111.8 | c.99_100delGC | p.Gln34fs | frameshift_variant | 1/67 | NP_002102.4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
HTT | ENST00000355072.11 | c.99_100delGC | p.Gln34fs | frameshift_variant | 1/67 | 1 | NM_001388492.1 | ENSP00000347184.5 |
Frequencies
GnomAD3 genomes AF: 0.0828 AC: 11599AN: 140094Hom.: 667 Cov.: 29
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GnomAD3 exomes AF: 0.00838 AC: 829AN: 98890Hom.: 23 AF XY: 0.00863 AC XY: 478AN XY: 55370
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GnomAD4 exome AF: 0.0212 AC: 28106AN: 1327640Hom.: 581 AF XY: 0.0218 AC XY: 14252AN XY: 654418
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GnomAD4 genome AF: 0.0828 AC: 11609AN: 140168Hom.: 669 Cov.: 29 AF XY: 0.0795 AC XY: 5444AN XY: 68500
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ClinVar
Significance: Benign
Submissions summary: Benign:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not specified Benign:1
Benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Mar 28, 2016 | 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: To date, only repeat expansions in this gene are known to be implicated in disease - |
Computational scores
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at