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Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP3 BS1

The NM_001388492.1(HTT):c.96_110del(p.Gln34_Gln38del) variant causes a inframe deletion change. The variant allele was found at a frequency of 0.00358 in 1,356,796 control chromosomes in the GnomAD database, including 37 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0029 (1 hom., cov: 0)
  • Exomes 𝑓: 0.0037 (36 hom.)
• Consequence: HTT NM_001388492.1 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 Likely_benign. Variant got -5 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_001388492.1
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00291 (384/131872) while in subpopulation SAS AF= 0.00512 (20/3910). AF 95% confidence interval is 0.0037. There are 1 homozygotes in gnomad4. There are 178 alleles in male gnomad4 subpopulation. Median coverage is 0. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HTT	NM_001388492.1	c.96_110del	p.Gln34_Gln38del	inframe_deletion	1/67	ENST00000355072.11
HTT	NM_002111.8	c.96_110del	p.Gln36_Gln40del	inframe_deletion	1/67

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HTT	ENST00000355072.11	c.96_110del	p.Gln34_Gln38del	inframe_deletion	1/67	1	NM_001388492.1	P2

Frequencies

GnomAD3 genomes AF: 0.00291 AC: 384 AN: 131774 Hom.: 1 Cov.: 0

Gnomad AFR AF: 0.00426

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00254

Gnomad ASJ AF: 0.00188

Gnomad EAS AF: 0.00169

Gnomad SAS AF: 0.00511

Gnomad FIN AF: 0.000679

Gnomad MID AF: 0.0149

Gnomad NFE AF: 0.00249

Gnomad OTH AF: 0.00223

GnomAD4 exome AF: 0.00366 AC: 4478 AN: 1224924 Hom.: 36 AF XY: 0.00369 AC XY: 2242 AN XY: 607674

Gnomad4 AFR exome AF: 0.00797

Gnomad4 AMR exome AF: 0.00443

Gnomad4 ASJ exome AF: 0.00387

Gnomad4 EAS exome AF: 0.00138

Gnomad4 SAS exome AF: 0.00794

Gnomad4 FIN exome AF: 0.000894

Gnomad4 NFE exome AF: 0.00333

Gnomad4 OTH exome AF: 0.00396

GnomAD4 genome AF: 0.00291 AC: 384 AN: 131872 Hom.: 1 Cov.: 0 AF XY: 0.00281 AC XY: 178 AN XY: 63422

Gnomad4 AFR AF: 0.00425

Gnomad4 AMR AF: 0.00254

Gnomad4 ASJ AF: 0.00188

Gnomad4 EAS AF: 0.00170

Gnomad4 SAS AF: 0.00512

Gnomad4 FIN AF: 0.000679

Gnomad4 NFE AF: 0.00249

Gnomad4 OTH AF: 0.00275

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Splicing

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;