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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.102_110dup(p.Gln36_Gln38dup) variant causes a inframe insertion change. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.030 (89 hom., cov: 0)
  • Exomes 𝑓: 0.034 (3844 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 amr. gnomad4 allele frequency = 0.0304 (4008/131858) while in subpopulation AMR AF= 0.046 (617/13410). AF 95% confidence interval is 0.043. There are 89 homozygotes in gnomad4. There are 1912 alleles in male gnomad4 subpopulation. Median coverage is 0. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 89 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HTT	NM_001388492.1	c.102_110dup	p.Gln36_Gln38dup	inframe_insertion	1/67	ENST00000355072.11
HTT	NM_002111.8	c.102_110dup	p.Gln36_Gln38dup	inframe_insertion	1/67

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HTT	ENST00000355072.11	c.102_110dup	p.Gln36_Gln38dup	inframe_insertion	1/67	1	NM_001388492.1	P2

Frequencies

GnomAD3 genomes AF: 0.0304 AC: 4007 AN: 131760 Hom.: 89 Cov.: 0

Gnomad AFR AF: 0.0205

Gnomad AMI AF: 0.00625

Gnomad AMR AF: 0.0461

Gnomad ASJ AF: 0.0295

Gnomad EAS AF: 0.00749

Gnomad SAS AF: 0.0240

Gnomad FIN AF: 0.0291

Gnomad MID AF: 0.0336

Gnomad NFE AF: 0.0351

Gnomad OTH AF: 0.0323

GnomAD4 exome AF: 0.0336 AC: 41184 AN: 1224512 Hom.: 3844 Cov.: 0 AF XY: 0.0336 AC XY: 20418 AN XY: 607470

Gnomad4 AFR exome AF: 0.0182

Gnomad4 AMR exome AF: 0.0490

Gnomad4 ASJ exome AF: 0.0264

Gnomad4 EAS exome AF: 0.00832

Gnomad4 SAS exome AF: 0.0280

Gnomad4 FIN exome AF: 0.0247

Gnomad4 NFE exome AF: 0.0353

Gnomad4 OTH exome AF: 0.0317

GnomAD4 genome AF: 0.0304 AC: 4008 AN: 131858 Hom.: 89 Cov.: 0 AF XY: 0.0301 AC XY: 1912 AN XY: 63420

Gnomad4 AFR AF: 0.0205

Gnomad4 AMR AF: 0.0460

Gnomad4 ASJ AF: 0.0295

Gnomad4 EAS AF: 0.00751

Gnomad4 SAS AF: 0.0238

Gnomad4 FIN AF: 0.0291

Gnomad4 NFE AF: 0.0351

Gnomad4 OTH AF: 0.0325

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;