4-3074876-CCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAG-CCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAG

Variant names:

• chr4-3074876-CCAGCAGCAG-C
• rs71180116
• NM_001388492.1:c.102_110delGCAGCAGCA

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP3 BA1

The NM_001388492.1(HTT):​c.102_110delGCAGCAGCA​(p.Gln35_Gln37del) variant causes a disruptive inframe deletion change. The variant allele was found at a frequency of 0.0331 in 1,329,742 control chromosomes in the GnomAD database, including 1,052 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.036 (153 hom., cov: 0)
  • Exomes 𝑓: 0.033 (899 hom.)
• Consequence: HTT NM_001388492.1 disruptive_inframe_deletion
• Clinical Significance: Not reported in ClinVar
• 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 -9 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_001388492.1
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0749 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HTT	NM_001388492.1	c.102_110delGCAGCAGCA	p.Gln35_Gln37del	disruptive_inframe_deletion	Exon 1 of 67	ENST00000355072.11	NP_001375421.1
HTT	NM_002111.8	c.102_110delGCAGCAGCA	p.Gln35_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.102_110delGCAGCAGCA	p.Gln35_Gln37del	disruptive_inframe_deletion	Exon 1 of 67	1	NM_001388492.1	ENSP00000347184.5

Frequencies

GnomAD3 genomes AF: 0.0358 AC: 4719 AN: 131666 Hom.: 152 Cov.: 0

Gnomad AFR AF: 0.0774

Gnomad AMI AF: 0.00250

Gnomad AMR AF: 0.0254

Gnomad ASJ AF: 0.0129

Gnomad EAS AF: 0.0247

Gnomad SAS AF: 0.0330

Gnomad FIN AF: 0.00652

Gnomad MID AF: 0.0299

Gnomad NFE AF: 0.0203

Gnomad OTH AF: 0.0352

GnomAD4 exome AF: 0.0328 AC: 39346 AN: 1197976 Hom.: 899 AF XY: 0.0329 AC XY: 19502 AN XY: 592888

African (AFR) AF: 0.0777 AC: 1995 AN: 25666

American (AMR) AF: 0.0277 AC: 823 AN: 29756

Ashkenazi Jewish (ASJ) AF: 0.0187 AC: 412 AN: 22038

East Asian (EAS) AF: 0.0419 AC: 1159 AN: 27674

South Asian (SAS) AF: 0.0443 AC: 2974 AN: 67172

European-Finnish (FIN) AF: 0.00999 AC: 320 AN: 32026

Middle Eastern (MID) AF: 0.0354 AC: 130 AN: 3668

European-Non Finnish (NFE) AF: 0.0318 AC: 29894 AN: 939308

Other (OTH) AF: 0.0323 AC: 1639 AN: 50668

GnomAD4 genome AF: 0.0359 AC: 4724 AN: 131766 Hom.: 153 Cov.: 0 AF XY: 0.0354 AC XY: 2243 AN XY: 63352

African (AFR) AF: 0.0773 AC: 2744 AN: 35476

American (AMR) AF: 0.0254 AC: 340 AN: 13400

Ashkenazi Jewish (ASJ) AF: 0.0129 AC: 41 AN: 3188

East Asian (EAS) AF: 0.0248 AC: 102 AN: 4118

South Asian (SAS) AF: 0.0333 AC: 130 AN: 3904

European-Finnish (FIN) AF: 0.00652 AC: 48 AN: 7360

Middle Eastern (MID) AF: 0.0278 AC: 7 AN: 252

European-Non Finnish (NFE) AF: 0.0203 AC: 1247 AN: 61456

Other (OTH) AF: 0.0348 AC: 63 AN: 1812

Alfa AF: 0.0170 Hom.: 452

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		5.7
Mutation Taster		=188/12	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs71180116; hg19: chr4-3076603;