rs754481229

Variant names:

• chr4-3074926-AGCAG-A
• rs754481229
• NM_001388492.1:c.102_105delGCAG

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 8P and 10B. PVS1 BP6_Moderate BS1 BS2

The NM_001388492.1(HTT):​c.102_105delGCAG​(p.Gln34HisfsTer66) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0161 in 141,172 control chromosomes in the GnomAD database, including 36 homozygotes. Variant has been reported in ClinVar as Benign (★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.016 (36 hom., cov: 25)
  • Exomes 𝑓: 0.011 (249 hom.)
  • Failed GnomAD Quality Control
• Consequence: HTT NM_001388492.1 frameshift
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.80

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 -2 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• BP6: Variant 4-3074926-AGCAG-A is Benign according to our data. Variant chr4-3074926-AGCAG-A is described in ClinVar as [Benign]. Clinvar id is 402953.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0161 (2277/141172) while in subpopulation NFE AF= 0.0237 (1528/64438). AF 95% confidence interval is 0.0227. There are 36 homozygotes in gnomad4. There are 1027 alleles in male gnomad4 subpopulation. Median coverage is 25. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 36 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HTT	NM_001388492.1	c.102_105delGCAG	p.Gln34HisfsTer66	frameshift_variant	Exon 1 of 67	ENST00000355072.11	NP_001375421.1
HTT	NM_002111.8	c.102_105delGCAG	p.Gln34HisfsTer66	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.102_105delGCAG	p.Gln34HisfsTer66	frameshift_variant	Exon 1 of 67	1	NM_001388492.1	ENSP00000347184.5

Frequencies

GnomAD3 genomes AF: 0.0162 AC: 2281 AN: 141102 Hom.: 36 Cov.: 25

Gnomad AFR AF: 0.00520

Gnomad AMI AF: 0.0108

Gnomad AMR AF: 0.0131

Gnomad ASJ AF: 0.0631

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0108

Gnomad FIN AF: 0.00518

Gnomad MID AF: 0.0362

Gnomad NFE AF: 0.0237

Gnomad OTH AF: 0.0215

GnomAD3 exomes AF: 0.00741 AC: 728 AN: 98246 Hom.: 19 AF XY: 0.00762 AC XY: 419 AN XY: 55008

Gnomad AFR exome AF: 0.00233

Gnomad AMR exome AF: 0.00402

Gnomad ASJ exome AF: 0.0230

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00564

Gnomad FIN exome AF: 0.00305

Gnomad NFE exome AF: 0.00883

Gnomad OTH exome AF: 0.00997

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0113 AC: 15025 AN: 1325628 Hom.: 249 AF XY: 0.0115 AC XY: 7510 AN XY: 653424

Gnomad4 AFR exome AF: 0.00323

Gnomad4 AMR exome AF: 0.00590

Gnomad4 ASJ exome AF: 0.0370

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00624

Gnomad4 FIN exome AF: 0.00720

Gnomad4 NFE exome AF: 0.0118

Gnomad4 OTH exome AF: 0.0134

GnomAD4 genome AF: 0.0161 AC: 2277 AN: 141172 Hom.: 36 Cov.: 25 AF XY: 0.0149 AC XY: 1027 AN XY: 68954

Gnomad4 AFR AF: 0.00521

Gnomad4 AMR AF: 0.0131

Gnomad4 ASJ AF: 0.0631

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0104

Gnomad4 FIN AF: 0.00518

Gnomad4 NFE AF: 0.0237

Gnomad4 OTH AF: 0.0214

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: rs754481229; hg19: chr4-3076653;