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Variant names:

• chr4-3074876-CCAG-C
• rs71180116
• NM_001388492.1:c.108_110delGCA

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP3 BP6_Moderate BA1

The NM_001388492.1(HTT):​c.108_110delGCA​(p.Gln37del) variant causes a disruptive inframe deletion change. The variant allele was found at a frequency of 0.144 in 1,348,862 control chromosomes in the GnomAD database, including 16,857 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.14 (1388 hom., cov: 0)
  • Exomes 𝑓: 0.14 (15469 hom.)
• Consequence: HTT NM_001388492.1 disruptive_inframe_deletion
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 5.65
• Publications: 6 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: Benign. The variant received -11 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_001388492.1
• BP6: Variant 4-3074876-CCAG-C is Benign according to our data. Variant chr4-3074876-CCAG-C is described in ClinVar as [Benign]. Clinvar id is 3910358.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.2 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HTT	NM_001388492.1	c.108_110delGCA	p.Gln37del	disruptive_inframe_deletion	Exon 1 of 67	ENST00000355072.11	NP_001375421.1
HTT	NM_002111.8	c.108_110delGCA	p.Gln37del	disruptive_inframe_deletion	Exon 1 of 67		NP_002102.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HTT	ENST00000355072.11	c.108_110delGCA	p.Gln37del	disruptive_inframe_deletion	Exon 1 of 67	1	NM_001388492.1	ENSP00000347184.5

Frequencies

GnomAD3 genomes AF: 0.139 AC: 18296 AN: 131632 Hom.: 1388 Cov.: 0

Gnomad AFR AF: 0.119

Gnomad AMI AF: 0.196

Gnomad AMR AF: 0.126

Gnomad ASJ AF: 0.115

Gnomad EAS AF: 0.213

Gnomad SAS AF: 0.127

Gnomad FIN AF: 0.163

Gnomad MID AF: 0.138

Gnomad NFE AF: 0.147

Gnomad OTH AF: 0.139

GnomAD4 exome AF: 0.144 AC: 175611 AN: 1217134 Hom.: 15469 AF XY: 0.144 AC XY: 86760 AN XY: 603820

African (AFR) AF: 0.118 AC: 3028 AN: 25608

American (AMR) AF: 0.126 AC: 3785 AN: 30072

Ashkenazi Jewish (ASJ) AF: 0.117 AC: 2631 AN: 22508

East Asian (EAS) AF: 0.230 AC: 6645 AN: 28912

South Asian (SAS) AF: 0.123 AC: 8848 AN: 71842

European-Finnish (FIN) AF: 0.157 AC: 5045 AN: 32150

Middle Eastern (MID) AF: 0.143 AC: 537 AN: 3746

European-Non Finnish (NFE) AF: 0.145 AC: 137876 AN: 950912

Other (OTH) AF: 0.140 AC: 7216 AN: 51384

GnomAD4 genome AF: 0.139 AC: 18302 AN: 131728 Hom.: 1388 Cov.: 0 AF XY: 0.140 AC XY: 8871 AN XY: 63356

African (AFR) AF: 0.119 AC: 4212 AN: 35484

American (AMR) AF: 0.126 AC: 1691 AN: 13402

Ashkenazi Jewish (ASJ) AF: 0.115 AC: 368 AN: 3190

East Asian (EAS) AF: 0.212 AC: 874 AN: 4122

South Asian (SAS) AF: 0.127 AC: 496 AN: 3906

European-Finnish (FIN) AF: 0.163 AC: 1200 AN: 7346

Middle Eastern (MID) AF: 0.151 AC: 38 AN: 252

European-Non Finnish (NFE) AF: 0.147 AC: 9014 AN: 61416

Other (OTH) AF: 0.139 AC: 253 AN: 1814

Alfa AF: 0.114 Hom.: 452

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Feb 16, 2025

Laboratory of Genetics, Children's Clinical University Hospital Latvia

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		5.7
Mutation Taster		=83/17	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: rs71180116; hg19: chr4-3076603; COSMIC: COSV61862357; COSMIC: COSV61862357;