4-3074876-CCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAG-CCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAG

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.81_110dupGCAGCAGCAGCAGCAGCAGCAGCAGCAGCA(p.Gln28_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 0.0040 ( 5 hom., cov: 0)

Exomes 𝑓: 0.0015 ( 19 hom. )

Failed GnomAD Quality Control

Consequence

HTT
NM_001388492.1 disruptive_inframe_insertion

Scores

Not classified

Clinical Significance

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

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 -17 ACMG points.

BP3

Nonframeshift variant in repetitive region in NM_001388492.1

BP6

Variant 4-3074876-C-CCAGCAGCAGCAGCAGCAGCAGCAGCAGCAG is Benign according to our data. Variant chr4-3074876-C-CCAGCAGCAGCAGCAGCAGCAGCAGCAGCAG is described in ClinVar as [Likely_benign]. Clinvar id is 2654593.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00405 (534/131868) while in subpopulation AMR AF = 0.00619 (83/13410). AF 95% confidence interval is 0.00511. There are 5 homozygotes in GnomAd4. There are 223 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 5 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HTT	NM_001388492.1 link	c.81_110dupGCAGCAGCAGCAGCAGCAGCAGCAGCAGCA	p.Gln28_Gln37dup	disruptive_inframe_insertion	Exon 1 of 67	ENST00000355072.11	NP_001375421.1
HTT	NM_002111.8 link	c.81_110dupGCAGCAGCAGCAGCAGCAGCAGCAGCAGCA	p.Gln28_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.81_110dupGCAGCAGCAGCAGCAGCAGCAGCAGCAGCA	p.Gln28_Gln37dup	disruptive_inframe_insertion	Exon 1 of 67	1	NM_001388492.1	ENSP00000347184.5		P42858

Frequencies

GnomAD3 genomes

AF:

0.00404

AC:

533

AN:

131770

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00311

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00620

Gnomad ASJ

AF:

0.00313

Gnomad EAS

AF:

0.00121

Gnomad SAS

AF:

0.00153

Gnomad FIN

AF:

0.00149

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00486

Gnomad OTH

AF:

0.00501

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00150

AC:

1834

AN:

1225782

Hom.:

Cov.:

AF XY:

0.00160

AC XY:

976

AN XY:

608110

show subpopulations

African (AFR)

AF:

0.00132

AC:

AN:

25812

American (AMR)

AF:

0.00330

AC:

100

AN:

30296

Ashkenazi Jewish (ASJ)

AF:

0.00185

AC:

AN:

22736

East Asian (EAS)

AF:

0.00148

AC:

AN:

29096

South Asian (SAS)

AF:

0.00192

AC:

139

AN:

72228

European-Finnish (FIN)

AF:

0.00215

AC:

AN:

32494

Middle Eastern (MID)

AF:

0.00185

AC:

AN:

3784

European-Non Finnish (NFE)

AF:

0.00137

AC:

1310

AN:

957500

Other (OTH)

AF:

0.00172

AC:

AN:

51836

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

143

191

239

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00405

AC:

534

AN:

131868

Hom.:

Cov.:

AF XY:

0.00352

AC XY:

223

AN XY:

63418

show subpopulations

African (AFR)

AF:

0.00313

AC:

111

AN:

35514

American (AMR)

AF:

0.00619

AC:

AN:

13410

Ashkenazi Jewish (ASJ)

AF:

0.00313

AC:

AN:

3190

East Asian (EAS)

AF:

0.00121

AC:

AN:

4124

South Asian (SAS)

AF:

0.00153

AC:

AN:

3910

European-Finnish (FIN)

AF:

0.00149

AC:

AN:

7368

Middle Eastern (MID)

AF:

0.00

AC:

AN:

252

European-Non Finnish (NFE)

AF:

0.00486

AC:

299

AN:

61484

Other (OTH)

AF:

0.00496

AC:

AN:

1816

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.546

Heterozygous variant carriers

109

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

ClinVar

Significance: Benign/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:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Dec 01, 2022

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

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-CCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAG

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