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Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP3 BA1

The NM_001388492.1(HTT):c.108_110dup(p.Gln37dup) variant causes a inframe insertion change. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.059 (287 hom., cov: 0)
  • Exomes 𝑓: 0.060 (2892 hom.)
  • Failed GnomAD Quality Control
• Consequence: HTT NM_001388492.1 inframe_insertion
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• 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
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0671 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HTT	NM_001388492.1	c.108_110dup	p.Gln37dup	inframe_insertion	1/67	ENST00000355072.11
HTT	NM_002111.8	c.108_110dup	p.Gln37dup	inframe_insertion	1/67

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HTT	ENST00000355072.11	c.108_110dup	p.Gln37dup	inframe_insertion	1/67	1	NM_001388492.1	P2

Frequencies

GnomAD3 genomes AF: 0.0586 AC: 7726 AN: 131746 Hom.: 287 Cov.: 0

Gnomad AFR AF: 0.0495

Gnomad AMI AF: 0.00625

Gnomad AMR AF: 0.0523

Gnomad ASJ AF: 0.0878

Gnomad EAS AF: 0.0244

Gnomad SAS AF: 0.0432

Gnomad FIN AF: 0.0515

Gnomad MID AF: 0.0485

Gnomad NFE AF: 0.0688

Gnomad OTH AF: 0.0535

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0597 AC: 73050 AN: 1223772 Hom.: 2892 Cov.: 0 AF XY: 0.0599 AC XY: 36343 AN XY: 607184

Gnomad4 AFR exome AF: 0.0417

Gnomad4 AMR exome AF: 0.0427

Gnomad4 ASJ exome AF: 0.0825

Gnomad4 EAS exome AF: 0.0229

Gnomad4 SAS exome AF: 0.0494

Gnomad4 FIN exome AF: 0.0498

Gnomad4 NFE exome AF: 0.0625

Gnomad4 OTH exome AF: 0.0579

GnomAD4 genome AF: 0.0586 AC: 7726 AN: 131844 Hom.: 287 Cov.: 0 AF XY: 0.0562 AC XY: 3566 AN XY: 63402

Gnomad4 AFR AF: 0.0492

Gnomad4 AMR AF: 0.0523

Gnomad4 ASJ AF: 0.0878

Gnomad4 EAS AF: 0.0245

Gnomad4 SAS AF: 0.0433

Gnomad4 FIN AF: 0.0515

Gnomad4 NFE AF: 0.0688

Gnomad4 OTH AF: 0.0551

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Huntington disease Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Al Jalila Children's Genomics Center, Al Jalila Childrens Speciality Hospital

Jan 06, 2020

- -

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;