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Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP3 BS1 BS2

The NM_001388492.1(HTT):c.105_110dup(p.Gln37_Gln38dup) variant causes a inframe insertion change. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.039 (121 hom., cov: 0)
  • Exomes 𝑓: 0.032 (2534 hom.)
• Consequence: HTT NM_001388492.1 inframe_insertion
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.84

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
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0388 (5117/131854) while in subpopulation AFR AF= 0.0451 (1603/35518). AF 95% confidence interval is 0.0433. There are 121 homozygotes in gnomad4. There are 2422 alleles in male gnomad4 subpopulation. Median coverage is 0. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 121 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HTT	NM_001388492.1	c.105_110dup	p.Gln37_Gln38dup	inframe_insertion	1/67	ENST00000355072.11
HTT	NM_002111.8	c.105_110dup	p.Gln37_Gln38dup	inframe_insertion	1/67

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HTT	ENST00000355072.11	c.105_110dup	p.Gln37_Gln38dup	inframe_insertion	1/67	1	NM_001388492.1	P2

Frequencies

GnomAD3 genomes AF: 0.0389 AC: 5122 AN: 131756 Hom.: 121 Cov.: 0

Gnomad AFR AF: 0.0453

Gnomad AMI AF: 0.0138

Gnomad AMR AF: 0.0394

Gnomad ASJ AF: 0.0254

Gnomad EAS AF: 0.0128

Gnomad SAS AF: 0.0223

Gnomad FIN AF: 0.0250

Gnomad MID AF: 0.0224

Gnomad NFE AF: 0.0406

Gnomad OTH AF: 0.0390

GnomAD4 exome AF: 0.0318 AC: 38958 AN: 1223798 Hom.: 2534 Cov.: 0 AF XY: 0.0322 AC XY: 19551 AN XY: 607118

Gnomad4 AFR exome AF: 0.0301

Gnomad4 AMR exome AF: 0.0306

Gnomad4 ASJ exome AF: 0.0224

Gnomad4 EAS exome AF: 0.00928

Gnomad4 SAS exome AF: 0.0277

Gnomad4 FIN exome AF: 0.0304

Gnomad4 NFE exome AF: 0.0332

Gnomad4 OTH exome AF: 0.0310

GnomAD4 genome AF: 0.0388 AC: 5117 AN: 131854 Hom.: 121 Cov.: 0 AF XY: 0.0382 AC XY: 2422 AN XY: 63406

Gnomad4 AFR AF: 0.0451

Gnomad4 AMR AF: 0.0392

Gnomad4 ASJ AF: 0.0254

Gnomad4 EAS AF: 0.0129

Gnomad4 SAS AF: 0.0220

Gnomad4 FIN AF: 0.0250

Gnomad4 NFE AF: 0.0406

Gnomad4 OTH AF: 0.0385

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;