Variant 4-3074876-CCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAG-CCAGCAGCAGCAGCAGCAGCAGCAGCAGCAG details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP3BA1

The NM_001388492.1(HTT):c.99_110delGCAGCAGCAGCA(p.Gln34_Gln37del) variant causes a disruptive 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 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.65

Variant links:

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]

HTT links:

HTT (HGNC:):

HTT links:

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ACMG classification

Classification made for transcript

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	Protein	UniProt
HTT	NM_001388492.1 linkuse as main transcript	c.99_110delGCAGCAGCAGCA	p.Gln34_Gln37del	disruptive_inframe_deletion	1/67	ENST00000355072.11	NP_001375421.1
HTT	NM_002111.8 linkuse as main transcript	c.99_110delGCAGCAGCAGCA	p.Gln34_Gln37del	disruptive_inframe_deletion	1/67		NP_002102.4	P42858

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HTT	ENST00000355072.11 linkuse as main transcript	c.99_110delGCAGCAGCAGCA	p.Gln34_Gln37del	disruptive_inframe_deletion	1/67	1	NM_001388492.1	ENSP00000347184.5		P42858

Frequencies

GnomAD3 genomes

AF:

0.0322

AC:

4242

AN:

131626

Hom.:

105

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.0331

AC XY:

2095

AN XY:

63348

show subpopulations

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

Name

Calibrated prediction

Score

Prediction

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over