4-3074876-CCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAG-CCAGCAGCAGCAGCAGCAGCAGCAG

Variant names:

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP3BP6_Very_StrongBS1BS2

The NM_001388492.1(HTT):c.90_110delGCAGCAGCAGCAGCAGCAGCA(p.Gln31_Gln37del) variant causes a disruptive inframe deletion change. The variant allele was found at a frequency of 0.00449 in 1,357,552 control chromosomes in the GnomAD database, including 41 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 0.0050 ( 3 hom., cov: 0)

Exomes 𝑓: 0.0044 ( 38 hom. )

Consequence

HTT
NM_001388492.1 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

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 -17 ACMG points.

BP3

Nonframeshift variant in repetitive region in NM_001388492.1

BP6

Variant 4-3074876-CCAGCAGCAGCAGCAGCAGCAG-C is Benign according to our data. Variant chr4-3074876-CCAGCAGCAGCAGCAGCAGCAG-C is described in ClinVar as [Likely_benign]. Clinvar id is 3770743.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00501 (660/131864) while in subpopulation NFE AF = 0.00795 (489/61478). AF 95% confidence interval is 0.00737. There are 3 homozygotes in GnomAd4. There are 301 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 3 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HTT	NM_001388492.1 link	c.90_110delGCAGCAGCAGCAGCAGCAGCA	p.Gln31_Gln37del	disruptive_inframe_deletion	Exon 1 of 67	ENST00000355072.11	NP_001375421.1
HTT	NM_002111.8 link	c.90_110delGCAGCAGCAGCAGCAGCAGCA	p.Gln31_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.90_110delGCAGCAGCAGCAGCAGCAGCA	p.Gln31_Gln37del	disruptive_inframe_deletion	Exon 1 of 67	1	NM_001388492.1	ENSP00000347184.5		P42858

Frequencies

GnomAD3 genomes

AF:

0.00499

AC:

658

AN:

131766

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00152

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00329

Gnomad ASJ

AF:

0.00157

Gnomad EAS

AF:

0.000242

Gnomad SAS

AF:

0.00256

Gnomad FIN

AF:

0.00570

Gnomad MID

AF:

0.00746

Gnomad NFE

AF:

0.00795

Gnomad OTH

AF:

0.00612

GnomAD4 exome

AF:

0.00444

AC:

5437

AN:

1225688

Hom.:

AF XY:

0.00446

AC XY:

2712

AN XY:

608064

show subpopulations

African (AFR)

AF:

0.00252

AC:

AN:

25808

American (AMR)

AF:

0.00162

AC:

AN:

30296

Ashkenazi Jewish (ASJ)

AF:

0.00180

AC:

AN:

22736

East Asian (EAS)

AF:

0.000722

AC:

AN:

29096

South Asian (SAS)

AF:

0.00312

AC:

225

AN:

72216

European-Finnish (FIN)

AF:

0.00569

AC:

185

AN:

32498

Middle Eastern (MID)

AF:

0.00581

AC:

AN:

3784

European-Non Finnish (NFE)

AF:

0.00478

AC:

4581

AN:

957420

Other (OTH)

AF:

0.00478

AC:

248

AN:

51834

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

Heterozygous variant carriers

210

421

631

842

1052

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00501

AC:

660

AN:

131864

Hom.:

Cov.:

AF XY:

0.00475

AC XY:

301

AN XY:

63420

show subpopulations

African (AFR)

AF:

0.00155

AC:

AN:

35522

American (AMR)

AF:

0.00328

AC:

AN:

13408

Ashkenazi Jewish (ASJ)

AF:

0.00157

AC:

AN:

3190

East Asian (EAS)

AF:

0.000242

AC:

AN:

4124

South Asian (SAS)

AF:

0.00256

AC:

AN:

3910

European-Finnish (FIN)

AF:

0.00570

AC:

AN:

7364

Middle Eastern (MID)

AF:

0.0119

AC:

AN:

252

European-Non Finnish (NFE)

AF:

0.00795

AC:

489

AN:

61478

Other (OTH)

AF:

0.00606

AC:

AN:

1816

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

102

127

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:2

Revision: criteria provided, multiple submitters, no conflicts

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

- -

not provided

Benign:1

Dec 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

HTT: BS2 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

5.7

Mutation Taster

=121/79

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-CCAGCAGCAGCAGCAGCAGCAGCAG

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