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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.81_110del(p.Gln29_Gln38del) variant causes a inframe deletion change. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000091 (0 hom., cov: 0)
  • Exomes 𝑓: 0.0013 (2 hom.)
  • Failed GnomAD Quality Control
• 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 nfe. gnomad4 allele frequency = 0.000091 (12/131882) while in subpopulation NFE AF= 0.00013 (8/61486). AF 95% confidence interval is 0.0000638. There are 0 homozygotes in gnomad4. There are 7 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.81_110del	p.Gln29_Gln38del	inframe_deletion	1/67	ENST00000355072.11
HTT	NM_002111.8	c.81_110del	p.Gln31_Gln40del	inframe_deletion	1/67

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HTT	ENST00000355072.11	c.81_110del	p.Gln29_Gln38del	inframe_deletion	1/67	1	NM_001388492.1	P2

Frequencies

GnomAD3 genomes AF: 0.0000911 AC: 12 AN: 131784 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.0000282

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000746

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000130

Gnomad OTH AF: 0.00111

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00132 AC: 1618 AN: 1225682 Hom.: 2 AF XY: 0.00128 AC XY: 776 AN XY: 608060

Gnomad4 AFR exome AF: 0.000387

Gnomad4 AMR exome AF: 0.000330

Gnomad4 ASJ exome AF: 0.000836

Gnomad4 EAS exome AF: 0.000137

Gnomad4 SAS exome AF: 0.000706

Gnomad4 FIN exome AF: 0.000369

Gnomad4 NFE exome AF: 0.00153

Gnomad4 OTH exome AF: 0.000810

GnomAD4 genome AF: 0.0000910 AC: 12 AN: 131882 Hom.: 0 Cov.: 0 AF XY: 0.000110 AC XY: 7 AN XY: 63426

Gnomad4 AFR AF: 0.0000281

Gnomad4 AMR AF: 0.0000746

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000130

Gnomad4 OTH AF: 0.00110

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;