4-3074876-CCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAG-CCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAG

Position:

• chr4-3074876-CCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAG-CCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAG

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP3 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• 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: Not reported in ClinVar
• Conservation: PhyloP100: 5.65

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 Benign. Variant got -9 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_001388492.1
• 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/exons	MANE	Protein	UniProt
HTT	NM_001388492.1	c.108_110delGCA	p.Gln37del	disruptive_inframe_deletion	1/67	ENST00000355072.11	NP_001375421.1
HTT	NM_002111.8	c.108_110delGCA	p.Gln37del	disruptive_inframe_deletion	1/67		NP_002102.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HTT	ENST00000355072.11	c.108_110delGCA	p.Gln37del	disruptive_inframe_deletion	1/67	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

Gnomad4 AFR exome AF: 0.118

Gnomad4 AMR exome AF: 0.126

Gnomad4 ASJ exome AF: 0.117

Gnomad4 EAS exome AF: 0.230

Gnomad4 SAS exome AF: 0.123

Gnomad4 FIN exome AF: 0.157

Gnomad4 NFE exome AF: 0.145

Gnomad4 OTH exome AF: 0.140

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

Gnomad4 AFR AF: 0.119

Gnomad4 AMR AF: 0.126

Gnomad4 ASJ AF: 0.115

Gnomad4 EAS AF: 0.212

Gnomad4 SAS AF: 0.127

Gnomad4 FIN AF: 0.163

Gnomad4 NFE AF: 0.147

Gnomad4 OTH AF: 0.139

ClinVar

Not reported in ClinVar

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: rs71180116; hg19: chr4-3076603;