Variant chr4-3074876-C-CCAGCAGCAGCAG details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP3BP6_ModerateBS1BS2

The NM_001388492.1(HTT):c.99_110dupGCAGCAGCAGCA(p.Gln34_Gln37dup) variant causes a disruptive inframe insertion change. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.027 ( 75 hom., cov: 0)

Exomes 𝑓: 0.010 ( 164 hom. )

Consequence

HTT
NM_001388492.1 disruptive_inframe_insertion

Scores

Not classified

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 4.84

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 -11 ACMG points.

BP3

Nonframeshift variant in repetitive region in NM_001388492.1

BP6

Variant 4-3074876-C-CCAGCAGCAGCAG is Benign according to our data. Variant chr4-3074876-C-CCAGCAGCAGCAG is described in ClinVar as [Benign]. Clinvar id is 1690808.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.0266 (3503/131854) while in subpopulation AMR AF= 0.0397 (532/13404). AF 95% confidence interval is 0.0369. There are 75 homozygotes in gnomad4. There are 1672 alleles in male gnomad4 subpopulation. Median coverage is 0. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 75 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HTT	NM_001388492.1 linkuse as main transcript	c.99_110dupGCAGCAGCAGCA	p.Gln34_Gln37dup	disruptive_inframe_insertion	1/67	ENST00000355072.11	NP_001375421.1
HTT	NM_002111.8 linkuse as main transcript	c.99_110dupGCAGCAGCAGCA	p.Gln34_Gln37dup	disruptive_inframe_insertion	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_110dupGCAGCAGCAGCA	p.Gln34_Gln37dup	disruptive_inframe_insertion	1/67	1	NM_001388492.1	ENSP00000347184.5		P42858

Frequencies

GnomAD3 genomes

AF:

0.0265

AC:

3497

AN:

131756

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0150

Gnomad AMI

AF:

0.0439

Gnomad AMR

AF:

0.0395

Gnomad ASJ

AF:

0.0166

Gnomad EAS

AF:

0.00701

Gnomad SAS

AF:

0.0189

Gnomad FIN

AF:

0.0271

Gnomad MID

AF:

0.0187

Gnomad NFE

AF:

0.0323

Gnomad OTH

AF:

0.0301

GnomAD4 exome

AF:

0.0103

AC:

12565

AN:

1225544

Hom.:

164

Cov.:

AF XY:

0.0111

AC XY:

6749

AN XY:

608000

show subpopulations

Gnomad4 AFR exome

AF:

0.00581

Gnomad4 AMR exome

AF:

0.0250

Gnomad4 ASJ exome

AF:

0.0128

Gnomad4 EAS exome

AF:

0.00385

Gnomad4 SAS exome

AF:

0.0115

Gnomad4 FIN exome

AF:

0.0238

Gnomad4 NFE exome

AF:

0.00929

Gnomad4 OTH exome

AF:

0.0136

GnomAD4 genome

AF:

0.0266

AC:

3503

AN:

131854

Hom.:

Cov.:

AF XY:

0.0264

AC XY:

1672

AN XY:

63404

show subpopulations

Gnomad4 AFR

AF:

0.0150

Gnomad4 AMR

AF:

0.0397

Gnomad4 ASJ

AF:

0.0166

Gnomad4 EAS

AF:

0.00703

Gnomad4 SAS

AF:

0.0194

Gnomad4 FIN

AF:

0.0271

Gnomad4 NFE

AF:

0.0323

Gnomad4 OTH

AF:

0.0297

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

See cases

Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Feb 16, 2020

ACMG classification criteria: BA1 -

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

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over