4-3074876-CCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAG-CCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAG

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.90_110dupGCAGCAGCAGCAGCAGCAGCA(p.Gln31_Gln37dup) variant causes a disruptive inframe insertion change. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.010 ( 11 hom., cov: 0)

Exomes 𝑓: 0.0036 ( 20 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-CCAGCAGCAGCAGCAGCAGCAG is Benign according to our data. Variant chr4-3074876-C-CCAGCAGCAGCAGCAGCAGCAG is described in ClinVar as [Likely_benign]. Clinvar id is 3910360.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0101 (1333/131868) while in subpopulation NFE AF = 0.0119 (730/61482). AF 95% confidence interval is 0.0112. There are 11 homozygotes in GnomAd4. There are 602 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 11 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HTT	NM_001388492.1 link	c.90_110dupGCAGCAGCAGCAGCAGCAGCA	p.Gln31_Gln37dup	disruptive_inframe_insertion	Exon 1 of 67	ENST00000355072.11	NP_001375421.1
HTT	NM_002111.8 link	c.90_110dupGCAGCAGCAGCAGCAGCAGCA	p.Gln31_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.90_110dupGCAGCAGCAGCAGCAGCAGCA	p.Gln31_Gln37dup	disruptive_inframe_insertion	Exon 1 of 67	1	NM_001388492.1	ENSP00000347184.5		P42858

Frequencies

GnomAD3 genomes

AF:

0.0101

AC:

1332

AN:

131770

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00833

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0116

Gnomad ASJ

AF:

0.00816

Gnomad EAS

AF:

0.00314

Gnomad SAS

AF:

0.00793

Gnomad FIN

AF:

0.00787

Gnomad MID

AF:

0.0112

Gnomad NFE

AF:

0.0119

Gnomad OTH

AF:

0.0117

GnomAD4 exome

AF:

0.00357

AC:

4374

AN:

1225744

Hom.:

Cov.:

AF XY:

0.00383

AC XY:

2330

AN XY:

608074

show subpopulations

African (AFR)

AF:

0.00260

AC:

AN:

25812

American (AMR)

AF:

0.00554

AC:

168

AN:

30302

Ashkenazi Jewish (ASJ)

AF:

0.00479

AC:

109

AN:

22732

East Asian (EAS)

AF:

0.00237

AC:

AN:

29088

South Asian (SAS)

AF:

0.00424

AC:

306

AN:

72222

European-Finnish (FIN)

AF:

0.00815

AC:

265

AN:

32498

Middle Eastern (MID)

AF:

0.00582

AC:

AN:

3780

European-Non Finnish (NFE)

AF:

0.00322

AC:

3085

AN:

957480

Other (OTH)

AF:

0.00546

AC:

283

AN:

51830

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

128

257

385

514

642

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0101

AC:

1333

AN:

131868

Hom.:

Cov.:

AF XY:

0.00949

AC XY:

602

AN XY:

63418

show subpopulations

African (AFR)

AF:

0.00831

AC:

295

AN:

35520

American (AMR)

AF:

0.0118

AC:

158

AN:

13410

Ashkenazi Jewish (ASJ)

AF:

0.00816

AC:

AN:

3188

East Asian (EAS)

AF:

0.00315

AC:

AN:

4124

South Asian (SAS)

AF:

0.00742

AC:

AN:

3908

European-Finnish (FIN)

AF:

0.00787

AC:

AN:

7368

Middle Eastern (MID)

AF:

0.0119

AC:

AN:

252

European-Non Finnish (NFE)

AF:

0.0119

AC:

730

AN:

61482

Other (OTH)

AF:

0.0116

AC:

AN:

1816

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.542

Heterozygous variant carriers

116

175

233

291

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

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

(source)

Splicing

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

Publications

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4-3074876-CCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAG-CCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAG

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