4-3074876-CCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAG-CCAGCAGCAGCAGCAGCAGCAGCAGCAGCAG

Variant names:

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP3BP6_ModerateBS1BS2

The NM_001388492.1(HTT):c.96_110delGCAGCAGCAGCAGCA(p.Gln33_Gln37del) variant causes a disruptive inframe deletion change. The variant allele was found at a frequency of 0.00358 in 1,356,796 control chromosomes in the GnomAD database, including 37 homozygotes. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.0029 ( 1 hom., cov: 0)

Exomes 𝑓: 0.0037 ( 36 hom. )

Consequence

HTT
NM_001388492.1 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 5.65

Publications

6 publications found

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 Gene-Disease associations (from GenCC):

Huntington disease
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae), Orphanet
Lopes-Maciel-Rodan syndrome
Inheritance: AR Classification: STRONG, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
juvenile Huntington disease
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

HTT links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -11 ACMG points.

BP3

Nonframeshift variant in repetitive region in NM_001388492.1

BP6

Variant 4-3074876-CCAGCAGCAGCAGCAG-C is Benign according to our data. Variant chr4-3074876-CCAGCAGCAGCAGCAG-C is described in ClinVar as [Benign]. Clinvar id is 3910357.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00291 (384/131872) while in subpopulation SAS AF = 0.00512 (20/3910). AF 95% confidence interval is 0.0037. There are 1 homozygotes in GnomAd4. There are 178 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 36 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HTT	NM_001388492.1 link	c.96_110delGCAGCAGCAGCAGCA	p.Gln33_Gln37del	disruptive_inframe_deletion	Exon 1 of 67	ENST00000355072.11	NP_001375421.1
HTT	NM_002111.8 link	c.96_110delGCAGCAGCAGCAGCA	p.Gln33_Gln37del	disruptive_inframe_deletion	Exon 1 of 67		NP_002102.4	P42858

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HTT	ENST00000355072.11 link	c.96_110delGCAGCAGCAGCAGCA	p.Gln33_Gln37del	disruptive_inframe_deletion	Exon 1 of 67	1	NM_001388492.1	ENSP00000347184.5		P42858

Frequencies

GnomAD3 genomes

AF:

0.00291

AC:

384

AN:

131774

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00426

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00254

Gnomad ASJ

AF:

0.00188

Gnomad EAS

AF:

0.00169

Gnomad SAS

AF:

0.00511

Gnomad FIN

AF:

0.000679

Gnomad MID

AF:

0.0149

Gnomad NFE

AF:

0.00249

Gnomad OTH

AF:

0.00223

GnomAD4 exome

AF:

0.00366

AC:

4478

AN:

1224924

Hom.:

AF XY:

0.00369

AC XY:

2242

AN XY:

607674

show subpopulations

African (AFR)

AF:

0.00797

AC:

205

AN:

25734

American (AMR)

AF:

0.00443

AC:

134

AN:

30220

Ashkenazi Jewish (ASJ)

AF:

0.00387

AC:

AN:

22720

East Asian (EAS)

AF:

0.00138

AC:

AN:

29090

South Asian (SAS)

AF:

0.00794

AC:

573

AN:

72158

European-Finnish (FIN)

AF:

0.000894

AC:

AN:

32454

Middle Eastern (MID)

AF:

0.00423

AC:

AN:

3782

European-Non Finnish (NFE)

AF:

0.00333

AC:

3188

AN:

956986

Other (OTH)

AF:

0.00396

AC:

205

AN:

51780

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

164

329

493

658

822

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00291

AC:

384

AN:

131872

Hom.:

Cov.:

AF XY:

0.00281

AC XY:

178

AN XY:

63422

show subpopulations

African (AFR)

AF:

0.00425

AC:

151

AN:

35518

American (AMR)

AF:

0.00254

AC:

AN:

13408

Ashkenazi Jewish (ASJ)

AF:

0.00188

AC:

AN:

3190

East Asian (EAS)

AF:

0.00170

AC:

AN:

4124

South Asian (SAS)

AF:

0.00512

AC:

AN:

3910

European-Finnish (FIN)

AF:

0.000679

AC:

AN:

7368

Middle Eastern (MID)

AF:

0.0119

AC:

AN:

252

European-Non Finnish (NFE)

AF:

0.00249

AC:

153

AN:

61486

Other (OTH)

AF:

0.00275

AC:

AN:

1816

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

452

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Benign:1

Feb 16, 2025

Laboratory of Genetics, Children's Clinical University Hospital Latvia

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

5.7

Mutation Taster

=188/12

polymorphism

(source)

Splicing

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

Publications

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4-3074876-CCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAG-CCAGCAGCAGCAGCAGCAGCAGCAGCAGCAG

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over