rs751281707

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 4P and 6B. PVS1_Strong BP6_Moderate BS2

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
• Publications: 0 publications found

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]

HTT Gene-Disease associations (from GenCC):

• Huntington disease

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae), Orphanet
• Lopes-Maciel-Rodan syndrome

  Inheritance: AR Classification: STRONG, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• juvenile Huntington disease

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -2 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. There are 5 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 VariationId is 402952.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd4 at 669 AR,AD gene

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

GnomAD2 exomes AF: 0.00838 AC: 829 AN: 98890 AF XY: 0.00863

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 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

African (AFR) AF: 0.0387 AC: 1048 AN: 27074

American (AMR) AF: 0.0240 AC: 789 AN: 32942

Ashkenazi Jewish (ASJ) AF: 0.0472 AC: 1110 AN: 23532

East Asian (EAS) AF: 0.0116 AC: 362 AN: 31340

South Asian (SAS) AF: 0.0162 AC: 1225 AN: 75468

European-Finnish (FIN) AF: 0.0343 AC: 1169 AN: 34068

Middle Eastern (MID) AF: 0.0437 AC: 175 AN: 4000

European-Non Finnish (NFE) AF: 0.0197 AC: 20528 AN: 1044314

Other (OTH) AF: 0.0310 AC: 1700 AN: 54902

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

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.158 AC: 5771 AN: 36444

American (AMR) AF: 0.0565 AC: 812 AN: 14372

Ashkenazi Jewish (ASJ) AF: 0.0927 AC: 306 AN: 3302

East Asian (EAS) AF: 0.0115 AC: 56 AN: 4854

South Asian (SAS) AF: 0.0215 AC: 98 AN: 4558

European-Finnish (FIN) AF: 0.0355 AC: 332 AN: 9344

Middle Eastern (MID) AF: 0.0638 AC: 18 AN: 282

European-Non Finnish (NFE) AF: 0.0632 AC: 4056 AN: 64204

Other (OTH) AF: 0.0758 AC: 147 AN: 1940

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

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

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.9
Mutation Taster		=192/8	polymorphism (auto)

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

Other links and lift over

dbSNP: rs751281707; hg19: chr4-3076650;