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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.99_110del(p.Gln35_Gln38del) variant causes a inframe deletion change. The variant allele was found at a frequency of 0.0427 in 1,356,160 control chromosomes in the GnomAD database, including 2,218 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.032 (108 hom., cov: 0)
  • Exomes 𝑓: 0.044 (2110 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 Benign. Variant got -9 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_001388492.1
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0603 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HTT	NM_001388492.1	c.99_110del	p.Gln35_Gln38del	inframe_deletion	1/67	ENST00000355072.11
HTT	NM_002111.8	c.99_110del	p.Gln37_Gln40del	inframe_deletion	1/67

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HTT	ENST00000355072.11	c.99_110del	p.Gln35_Gln38del	inframe_deletion	1/67	1	NM_001388492.1	P2

Frequencies

GnomAD3 genomes AF: 0.0322 AC: 4242 AN: 131626 Hom.: 105 Cov.: 0

Gnomad AFR AF: 0.0188

Gnomad AMI AF: 0.0163

Gnomad AMR AF: 0.0635

Gnomad ASJ AF: 0.0285

Gnomad EAS AF: 0.0114

Gnomad SAS AF: 0.0269

Gnomad FIN AF: 0.0527

Gnomad MID AF: 0.0485

Gnomad NFE AF: 0.0323

Gnomad OTH AF: 0.0463

GnomAD4 exome AF: 0.0438 AC: 53612 AN: 1224436 Hom.: 2110 AF XY: 0.0428 AC XY: 25979 AN XY: 607438

Gnomad4 AFR exome AF: 0.0966

Gnomad4 AMR exome AF: 0.0864

Gnomad4 ASJ exome AF: 0.0298

Gnomad4 EAS exome AF: 0.00908

Gnomad4 SAS exome AF: 0.0294

Gnomad4 FIN exome AF: 0.0531

Gnomad4 NFE exome AF: 0.0434

Gnomad4 OTH exome AF: 0.0413

GnomAD4 genome AF: 0.0322 AC: 4246 AN: 131724 Hom.: 108 Cov.: 0 AF XY: 0.0331 AC XY: 2095 AN XY: 63348

Gnomad4 AFR AF: 0.0189

Gnomad4 AMR AF: 0.0638

Gnomad4 ASJ AF: 0.0285

Gnomad4 EAS AF: 0.0114

Gnomad4 SAS AF: 0.0266

Gnomad4 FIN AF: 0.0527

Gnomad4 NFE AF: 0.0323

Gnomad4 OTH AF: 0.0452

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;