rs751281707

Variant names:

• chr4-3074923-AGC-A
• rs751281707
• NM_001388492.1:c.99_100delGC

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 4P and 10B. PVS1_Strong BP6_Moderate BA1

The NM_001388492.1(HTT):​c.99_100delGC​(p.Gln34AlafsTer48) 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
• Clinical Significance: Benign criteria provided, single submitter B:1
• 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]

ACMG classification

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 rank	MANE	Protein	UniProt
HTT	NM_001388492.1	c.99_100delGC	p.Gln34AlafsTer48	frameshift_variant	Exon 1 of 67	ENST00000355072.11	NP_001375421.1
HTT	NM_002111.8	c.99_100delGC	p.Gln34AlafsTer48	frameshift_variant	Exon 1 of 67		NP_002102.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HTT	ENST00000355072.11	c.99_100delGC	p.Gln34AlafsTer48	frameshift_variant	Exon 1 of 67	1	NM_001388492.1	ENSP00000347184.5

Frequencies

GnomAD3 genomes AF: 0.0828 AC: 11599 AN: 140094 Hom.: 667 Cov.: 29

Gnomad AFR AF: 0.158

Gnomad AMI AF: 0.0150

Gnomad AMR AF: 0.0566

Gnomad ASJ AF: 0.0927

Gnomad EAS AF: 0.0115

Gnomad SAS AF: 0.0224

Gnomad FIN AF: 0.0355

Gnomad MID AF: 0.0625

Gnomad NFE AF: 0.0632

Gnomad OTH AF: 0.0769

GnomAD3 exomes AF: 0.00838 AC: 829 AN: 98890 Hom.: 23 AF XY: 0.00863 AC XY: 478 AN XY: 55370

Gnomad AFR exome AF: 0.00398

Gnomad AMR exome AF: 0.00647

Gnomad ASJ exome AF: 0.0231

Gnomad EAS exome AF: 0.000413

Gnomad SAS exome AF: 0.00579

Gnomad FIN exome AF: 0.00386

Gnomad NFE exome AF: 0.00973

Gnomad OTH exome AF: 0.0106

GnomAD4 exome AF: 0.0212 AC: 28106 AN: 1327640 Hom.: 581 AF XY: 0.0218 AC XY: 14252 AN XY: 654418

Gnomad4 AFR exome AF: 0.0387

Gnomad4 AMR exome AF: 0.0240

Gnomad4 ASJ exome AF: 0.0472

Gnomad4 EAS exome AF: 0.0116

Gnomad4 SAS exome AF: 0.0162

Gnomad4 FIN exome AF: 0.0343

Gnomad4 NFE exome AF: 0.0197

Gnomad4 OTH exome AF: 0.0310

GnomAD4 genome AF: 0.0828 AC: 11609 AN: 140168 Hom.: 669 Cov.: 29 AF XY: 0.0795 AC XY: 5444 AN XY: 68500

Gnomad4 AFR AF: 0.158

Gnomad4 AMR AF: 0.0565

Gnomad4 ASJ AF: 0.0927

Gnomad4 EAS AF: 0.0115

Gnomad4 SAS AF: 0.0215

Gnomad4 FIN AF: 0.0355

Gnomad4 NFE AF: 0.0632

Gnomad4 OTH AF: 0.0758

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs751281707; hg19: chr4-3076650;