4-3074876-CCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAG-CCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAG

Variant summary

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

The NM_001388492.1(HTT):c.102_110del(p.Gln36_Gln38del) variant causes a inframe deletion change. The variant allele was found at a frequency of 0.0331 in 1,329,742 control chromosomes in the GnomAD database, including 1,052 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.036 (153 hom., cov: 0)
  • Exomes 𝑓: 0.033 (899 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 (AFR) allele frequency at 95% confidence interval = 0.0749 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HTT	NM_001388492.1	c.102_110del	p.Gln36_Gln38del	inframe_deletion	1/67	ENST00000355072.11
HTT	NM_002111.8	c.102_110del	p.Gln38_Gln40del	inframe_deletion	1/67

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HTT	ENST00000355072.11	c.102_110del	p.Gln36_Gln38del	inframe_deletion	1/67	1	NM_001388492.1	P2

Frequencies

GnomAD3 genomes AF: 0.0358 AC: 4719 AN: 131666 Hom.: 152 Cov.: 0

Gnomad AFR AF: 0.0774

Gnomad AMI AF: 0.00250

Gnomad AMR AF: 0.0254

Gnomad ASJ AF: 0.0129

Gnomad EAS AF: 0.0247

Gnomad SAS AF: 0.0330

Gnomad FIN AF: 0.00652

Gnomad MID AF: 0.0299

Gnomad NFE AF: 0.0203

Gnomad OTH AF: 0.0352

GnomAD4 exome AF: 0.0328 AC: 39346 AN: 1197976 Hom.: 899 AF XY: 0.0329 AC XY: 19502 AN XY: 592888

Gnomad4 AFR exome AF: 0.0777

Gnomad4 AMR exome AF: 0.0277

Gnomad4 ASJ exome AF: 0.0187

Gnomad4 EAS exome AF: 0.0419

Gnomad4 SAS exome AF: 0.0443

Gnomad4 FIN exome AF: 0.00999

Gnomad4 NFE exome AF: 0.0318

Gnomad4 OTH exome AF: 0.0323

GnomAD4 genome AF: 0.0359 AC: 4724 AN: 131766 Hom.: 153 Cov.: 0 AF XY: 0.0354 AC XY: 2243 AN XY: 63352

Gnomad4 AFR AF: 0.0773

Gnomad4 AMR AF: 0.0254

Gnomad4 ASJ AF: 0.0129

Gnomad4 EAS AF: 0.0248

Gnomad4 SAS AF: 0.0333

Gnomad4 FIN AF: 0.00652

Gnomad4 NFE AF: 0.0203

Gnomad4 OTH AF: 0.0348

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;