4-3074876-CCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAG-CCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAG

Variant names:

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP3BP6_ModerateBA1

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. 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 Likely benign (★).

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

Likely 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-CCAGCAGCAGCAG-C is Benign according to our data. Variant chr4-3074876-CCAGCAGCAGCAG-C is described in ClinVar as [Likely_benign]. Clinvar id is 3910359.Status of the report is criteria_provided_single_submitter, 1 stars.

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 rank	MANE	Protein	UniProt
HTT	NM_001388492.1 link	c.99_110delGCAGCAGCAGCA	p.Gln34_Gln37del	disruptive_inframe_deletion	Exon 1 of 67	ENST00000355072.11	NP_001375421.1
HTT	NM_002111.8 link	c.99_110delGCAGCAGCAGCA	p.Gln34_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.99_110delGCAGCAGCAGCA	p.Gln34_Gln37del	disruptive_inframe_deletion	Exon 1 of 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

African (AFR)

AF:

0.0966

AC:

2482

AN:

25706

American (AMR)

AF:

0.0864

AC:

2604

AN:

30146

Ashkenazi Jewish (ASJ)

AF:

0.0298

AC:

676

AN:

22708

East Asian (EAS)

AF:

0.00908

AC:

264

AN:

29068

South Asian (SAS)

AF:

0.0294

AC:

2119

AN:

72080

European-Finnish (FIN)

AF:

0.0531

AC:

1723

AN:

32470

Middle Eastern (MID)

AF:

0.0341

AC:

129

AN:

3782

European-Non Finnish (NFE)

AF:

0.0434

AC:

41479

AN:

956726

Other (OTH)

AF:

0.0413

AC:

2136

AN:

51750

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

1876

3752

5627

7503

9379

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0322

AC:

4246

AN:

131724

Hom.:

108

Cov.:

AF XY:

0.0331

AC XY:

2095

AN XY:

63348

show subpopulations

African (AFR)

AF:

0.0189

AC:

669

AN:

35464

American (AMR)

AF:

0.0638

AC:

855

AN:

13398

Ashkenazi Jewish (ASJ)

AF:

0.0285

AC:

AN:

3188

East Asian (EAS)

AF:

0.0114

AC:

AN:

4124

South Asian (SAS)

AF:

0.0266

AC:

104

AN:

3908

European-Finnish (FIN)

AF:

0.0527

AC:

388

AN:

7360

Middle Eastern (MID)

AF:

0.0437

AC:

AN:

252

European-Non Finnish (NFE)

AF:

0.0323

AC:

1986

AN:

61418

Other (OTH)

AF:

0.0452

AC:

AN:

1814

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

165

329

494

658

823

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0414

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

5.7

Mutation Taster

=194/6

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-CCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAG

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