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Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP3 BS1

The NM_001388492.1(HTT):c.93_110del(p.Gln33_Gln38del) variant causes a inframe deletion change. The variant allele was found at a frequency of 0.000852 in 1,357,712 control chromosomes in the GnomAD database, including 3 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0014 (1 hom., cov: 0)
  • Exomes 𝑓: 0.00079 (2 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 Likely_benign. Variant got -5 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_001388492.1
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00144 (190/131876) while in subpopulation SAS AF= 0.00409 (16/3910). AF 95% confidence interval is 0.00257. There are 1 homozygotes in gnomad4. There are 106 alleles in male gnomad4 subpopulation. Median coverage is 0. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HTT	NM_001388492.1	c.93_110del	p.Gln33_Gln38del	inframe_deletion	1/67	ENST00000355072.11
HTT	NM_002111.8	c.93_110del	p.Gln35_Gln40del	inframe_deletion	1/67

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HTT	ENST00000355072.11	c.93_110del	p.Gln33_Gln38del	inframe_deletion	1/67	1	NM_001388492.1	P2

Frequencies

GnomAD3 genomes AF: 0.00140 AC: 185 AN: 131778 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.00277

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00187

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00193

Gnomad SAS AF: 0.00358

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000520

Gnomad OTH AF: 0.00445

GnomAD4 exome AF: 0.000789 AC: 967 AN: 1225836 Hom.: 2 AF XY: 0.000801 AC XY: 487 AN XY: 608130

Gnomad4 AFR exome AF: 0.00353

Gnomad4 AMR exome AF: 0.00195

Gnomad4 ASJ exome AF: 0.000176

Gnomad4 EAS exome AF: 0.000619

Gnomad4 SAS exome AF: 0.00222

Gnomad4 FIN exome AF: 0.000185

Gnomad4 NFE exome AF: 0.000597

Gnomad4 OTH exome AF: 0.00106

GnomAD4 genome AF: 0.00144 AC: 190 AN: 131876 Hom.: 1 Cov.: 0 AF XY: 0.00167 AC XY: 106 AN XY: 63422

Gnomad4 AFR AF: 0.00282

Gnomad4 AMR AF: 0.00186

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00194

Gnomad4 SAS AF: 0.00409

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000520

Gnomad4 OTH AF: 0.00496

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;