4-3074876-CCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAG-CCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAG

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PP5_ModerateBP3BS1_SupportingBS2

The NM_001388492.1(HTT):c.84_110dupGCAGCAGCAGCAGCAGCAGCAGCAGCA(p.Gln29_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 Pathogenic (★).

Frequency

Genomes: 𝑓 0.0058 ( 7 hom., cov: 0)

Exomes 𝑓: 0.0020 ( 29 hom. )

Failed GnomAD Quality Control

Consequence

HTT
NM_001388492.1 disruptive_inframe_insertion

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, single submitter P: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: Likely_benign. The variant received -4 ACMG points.

PP5

Variant 4-3074876-C-CCAGCAGCAGCAGCAGCAGCAGCAGCAG is Pathogenic according to our data. Variant chr4-3074876-C-CCAGCAGCAGCAGCAGCAGCAGCAGCAG is described in ClinVar as [Pathogenic]. Clinvar id is 3359130.Status of the report is criteria_provided_single_submitter, 1 stars.

BP3

Nonframeshift variant in repetitive region in NM_001388492.1

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00584 (770/131874) while in subpopulation AMR AF = 0.0088 (118/13410). AF 95% confidence interval is 0.00751. There are 7 homozygotes in GnomAd4. There are 376 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High Homozygotes in GnomAd4 at 7 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HTT	NM_001388492.1 link	c.84_110dupGCAGCAGCAGCAGCAGCAGCAGCAGCA	p.Gln29_Gln37dup	disruptive_inframe_insertion	Exon 1 of 67	ENST00000355072.11	NP_001375421.1
HTT	NM_002111.8 link	c.84_110dupGCAGCAGCAGCAGCAGCAGCAGCAGCA	p.Gln29_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.84_110dupGCAGCAGCAGCAGCAGCAGCAGCAGCA	p.Gln29_Gln37dup	disruptive_inframe_insertion	Exon 1 of 67	1	NM_001388492.1	ENSP00000347184.5		P42858

Frequencies

GnomAD3 genomes

AF:

0.00583

AC:

768

AN:

131776

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00469

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00881

Gnomad ASJ

AF:

0.00596

Gnomad EAS

AF:

0.00169

Gnomad SAS

AF:

0.00307

Gnomad FIN

AF:

0.00367

Gnomad MID

AF:

0.0149

Gnomad NFE

AF:

0.00657

Gnomad OTH

AF:

0.00612

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00200

AC:

2452

AN:

1225710

Hom.:

Cov.:

AF XY:

0.00215

AC XY:

1308

AN XY:

608048

show subpopulations

African (AFR)

AF:

0.00139

AC:

AN:

25810

American (AMR)

AF:

0.00340

AC:

103

AN:

30288

Ashkenazi Jewish (ASJ)

AF:

0.00255

AC:

AN:

22734

East Asian (EAS)

AF:

0.00175

AC:

AN:

29094

South Asian (SAS)

AF:

0.00234

AC:

169

AN:

72222

European-Finnish (FIN)

AF:

0.00397

AC:

129

AN:

32500

Middle Eastern (MID)

AF:

0.00159

AC:

AN:

3782

European-Non Finnish (NFE)

AF:

0.00183

AC:

1753

AN:

957450

Other (OTH)

AF:

0.00284

AC:

147

AN:

51830

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

126

190

253

316

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00584

AC:

770

AN:

131874

Hom.:

Cov.:

AF XY:

0.00593

AC XY:

376

AN XY:

63418

show subpopulations

African (AFR)

AF:

0.00470

AC:

167

AN:

35522

American (AMR)

AF:

0.00880

AC:

118

AN:

13410

Ashkenazi Jewish (ASJ)

AF:

0.00596

AC:

AN:

3190

East Asian (EAS)

AF:

0.00170

AC:

AN:

4124

South Asian (SAS)

AF:

0.00307

AC:

AN:

3910

European-Finnish (FIN)

AF:

0.00367

AC:

AN:

7366

Middle Eastern (MID)

AF:

0.0159

AC:

AN:

252

European-Non Finnish (NFE)

AF:

0.00659

AC:

405

AN:

61484

Other (OTH)

AF:

0.00606

AC:

AN:

1816

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.555

Heterozygous variant carriers

129

161

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

452

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Huntington disease

Pathogenic:1

Sep 06, 2023

Institute of Human Genetics, University of Leipzig Medical Center

Significance:Pathogenic

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-CCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAG

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