4-3074876-CCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAG-CCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAG

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.102_110dupGCAGCAGCA(p.Gln35_Gln37dup) variant causes a disruptive inframe insertion change. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.030 ( 89 hom., cov: 0)

Exomes 𝑓: 0.034 ( 3844 hom. )

Consequence

HTT
NM_001388492.1 disruptive_inframe_insertion

Scores

Not classified

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 4.84

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-C-CCAGCAGCAG is Benign according to our data. Variant chr4-3074876-C-CCAGCAGCAG is described in ClinVar as [Likely_benign]. Clinvar id is 3910361.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.0304 (4008/131858) while in subpopulation AMR AF = 0.046 (617/13410). AF 95% confidence interval is 0.043. There are 89 homozygotes in GnomAd4. There are 1912 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 89 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HTT	NM_001388492.1 link	c.102_110dupGCAGCAGCA	p.Gln35_Gln37dup	disruptive_inframe_insertion	Exon 1 of 67	ENST00000355072.11	NP_001375421.1
HTT	NM_002111.8 link	c.102_110dupGCAGCAGCA	p.Gln35_Gln37dup	disruptive_inframe_insertion	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.102_110dupGCAGCAGCA	p.Gln35_Gln37dup	disruptive_inframe_insertion	Exon 1 of 67	1	NM_001388492.1	ENSP00000347184.5		P42858

Frequencies

GnomAD3 genomes

AF:

0.0304

AC:

4007

AN:

131760

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0205

Gnomad AMI

AF:

0.00625

Gnomad AMR

AF:

0.0461

Gnomad ASJ

AF:

0.0295

Gnomad EAS

AF:

0.00749

Gnomad SAS

AF:

0.0240

Gnomad FIN

AF:

0.0291

Gnomad MID

AF:

0.0336

Gnomad NFE

AF:

0.0351

Gnomad OTH

AF:

0.0323

GnomAD4 exome

AF:

0.0336

AC:

41184

AN:

1224512

Hom.:

3844

Cov.:

AF XY:

0.0336

AC XY:

20418

AN XY:

607470

show subpopulations

African (AFR)

AF:

0.0182

AC:

469

AN:

25788

American (AMR)

AF:

0.0490

AC:

1483

AN:

30260

Ashkenazi Jewish (ASJ)

AF:

0.0264

AC:

599

AN:

22718

East Asian (EAS)

AF:

0.00832

AC:

242

AN:

29094

South Asian (SAS)

AF:

0.0280

AC:

2022

AN:

72176

European-Finnish (FIN)

AF:

0.0247

AC:

803

AN:

32468

Middle Eastern (MID)

AF:

0.0315

AC:

119

AN:

3778

European-Non Finnish (NFE)

AF:

0.0353

AC:

33807

AN:

956432

Other (OTH)

AF:

0.0317

AC:

1640

AN:

51798

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

1256

2512

3767

5023

6279

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0304

AC:

4008

AN:

131858

Hom.:

Cov.:

AF XY:

0.0301

AC XY:

1912

AN XY:

63420

show subpopulations

African (AFR)

AF:

0.0205

AC:

728

AN:

35518

American (AMR)

AF:

0.0460

AC:

617

AN:

13410

Ashkenazi Jewish (ASJ)

AF:

0.0295

AC:

AN:

3190

East Asian (EAS)

AF:

0.00751

AC:

AN:

4126

South Asian (SAS)

AF:

0.0238

AC:

AN:

3910

European-Finnish (FIN)

AF:

0.0291

AC:

214

AN:

7364

Middle Eastern (MID)

AF:

0.0357

AC:

AN:

252

European-Non Finnish (NFE)

AF:

0.0351

AC:

2158

AN:

61472

Other (OTH)

AF:

0.0325

AC:

AN:

1816

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.531

Heterozygous variant carriers

164

329

493

658

822

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0133

Hom.:

452

ClinVar

Significance: Likely 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:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

4.8

Mutation Taster

=80/20

polymorphism (auto)

(source)

Splicing

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

Publications

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4-3074876-CCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAG-CCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAG

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