4-3074876-CCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAG-CCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAG

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP3 BP6 BA1

The NM_001388492.1(HTT):c.105_110del(p.Gln37_Gln38del) variant causes a inframe deletion change. The variant allele was found at a frequency of 0.245 in 1,348,998 control chromosomes in the GnomAD database, including 35,626 homozygotes. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.20 (3269 hom., cov: 0)
  • Exomes 𝑓: 0.25 (32357 hom.)
• Consequence: HTT NM_001388492.1 inframe_deletion
• Clinical Significance: Benign/Likely benign no assertion criteria provided B:2
• 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 -10 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_001388492.1
• BP6: Variant 4-3074876-CCAGCAG-C is Benign according to our data. Variant chr4-3074876-CCAGCAG-C is described in ClinVar as [Likely_benign]. Clinvar id is 1328024.Status of the report is no_assertion_criteria_provided, 0 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.396 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HTT	NM_001388492.1	c.105_110del	p.Gln37_Gln38del	inframe_deletion	1/67	ENST00000355072.11
HTT	NM_002111.8	c.105_110del	p.Gln39_Gln40del	inframe_deletion	1/67

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HTT	ENST00000355072.11	c.105_110del	p.Gln37_Gln38del	inframe_deletion	1/67	1	NM_001388492.1	P2

Frequencies

GnomAD3 genomes AF: 0.203 AC: 26654 AN: 131118 Hom.: 3269 Cov.: 0

Gnomad AFR AF: 0.117

Gnomad AMI AF: 0.438

Gnomad AMR AF: 0.198

Gnomad ASJ AF: 0.293

Gnomad EAS AF: 0.315

Gnomad SAS AF: 0.413

Gnomad FIN AF: 0.176

Gnomad MID AF: 0.384

Gnomad NFE AF: 0.228

Gnomad OTH AF: 0.225

GnomAD4 exome AF: 0.249 AC: 303610 AN: 1217784 Hom.: 32357 AF XY: 0.252 AC XY: 152292 AN XY: 603946

Gnomad4 AFR exome AF: 0.121

Gnomad4 AMR exome AF: 0.212

Gnomad4 ASJ exome AF: 0.271

Gnomad4 EAS exome AF: 0.313

Gnomad4 SAS exome AF: 0.364

Gnomad4 FIN exome AF: 0.176

Gnomad4 NFE exome AF: 0.245

Gnomad4 OTH exome AF: 0.247

GnomAD4 genome AF: 0.203 AC: 26660 AN: 131214 Hom.: 3269 Cov.: 0 AF XY: 0.206 AC XY: 13028 AN XY: 63102

Gnomad4 AFR AF: 0.117

Gnomad4 AMR AF: 0.198

Gnomad4 ASJ AF: 0.293

Gnomad4 EAS AF: 0.315

Gnomad4 SAS AF: 0.413

Gnomad4 FIN AF: 0.176

Gnomad4 NFE AF: 0.228

Gnomad4 OTH AF: 0.223

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: no assertion criteria provided

Submissions by phenotype

not specified Benign:1

Benign, no assertion criteria provided

clinical testing

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

-

- -

not provided Benign:1

Likely benign, no assertion criteria provided

clinical testing

Genome Diagnostics Laboratory, University Medical Center Utrecht

-

- -

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;