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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.90_110del(p.Gln32_Gln38del) variant causes a inframe deletion change. The variant allele was found at a frequency of 0.00449 in 1,357,552 control chromosomes in the GnomAD database, including 41 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0050 (3 hom., cov: 0)
  • Exomes 𝑓: 0.0044 (38 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
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00501 (660/131864) while in subpopulation NFE AF= 0.00795 (489/61478). AF 95% confidence interval is 0.00737. There are 3 homozygotes in gnomad4. There are 301 alleles in male gnomad4 subpopulation. Median coverage is 0. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 3 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HTT	NM_001388492.1	c.90_110del	p.Gln32_Gln38del	inframe_deletion	1/67	ENST00000355072.11
HTT	NM_002111.8	c.90_110del	p.Gln34_Gln40del	inframe_deletion	1/67

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HTT	ENST00000355072.11	c.90_110del	p.Gln32_Gln38del	inframe_deletion	1/67	1	NM_001388492.1	P2

Frequencies

GnomAD3 genomes AF: 0.00499 AC: 658 AN: 131766 Hom.: 3 Cov.: 0

Gnomad AFR AF: 0.00152

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00329

Gnomad ASJ AF: 0.00157

Gnomad EAS AF: 0.000242

Gnomad SAS AF: 0.00256

Gnomad FIN AF: 0.00570

Gnomad MID AF: 0.00746

Gnomad NFE AF: 0.00795

Gnomad OTH AF: 0.00612

GnomAD4 exome AF: 0.00444 AC: 5437 AN: 1225688 Hom.: 38 AF XY: 0.00446 AC XY: 2712 AN XY: 608064

Gnomad4 AFR exome AF: 0.00252

Gnomad4 AMR exome AF: 0.00162

Gnomad4 ASJ exome AF: 0.00180

Gnomad4 EAS exome AF: 0.000722

Gnomad4 SAS exome AF: 0.00312

Gnomad4 FIN exome AF: 0.00569

Gnomad4 NFE exome AF: 0.00478

Gnomad4 OTH exome AF: 0.00478

GnomAD4 genome AF: 0.00501 AC: 660 AN: 131864 Hom.: 3 Cov.: 0 AF XY: 0.00475 AC XY: 301 AN XY: 63420

Gnomad4 AFR AF: 0.00155

Gnomad4 AMR AF: 0.00328

Gnomad4 ASJ AF: 0.00157

Gnomad4 EAS AF: 0.000242

Gnomad4 SAS AF: 0.00256

Gnomad4 FIN AF: 0.00570

Gnomad4 NFE AF: 0.00795

Gnomad4 OTH AF: 0.00606

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;