4-3074876-CCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAG-CCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAG

Variant names:

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_ModerateBS1BS2

The NM_001388492.1(HTT):c.105_110dupGCAGCA(p.Gln36_Gln37dup) variant causes a disruptive inframe insertion change. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.039 ( 121 hom., cov: 0)

Exomes 𝑓: 0.032 ( 2534 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: Orphanet, Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae)
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

new If you want to explore the variant's impact on the transcript NM_001388492.1, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

BP6

Variant 4-3074876-C-CCAGCAG is Benign according to our data. Variant chr4-3074876-C-CCAGCAG is described in ClinVar as Likely_benign. ClinVar VariationId is 3910356.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0388 (5117/131854) while in subpopulation AFR AF = 0.0451 (1603/35518). AF 95% confidence interval is 0.0433. There are 121 homozygotes in GnomAd4. There are 2422 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 121 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001388492.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HTT	NM_001388492.1	MANE Select	c.105_110dupGCAGCA	p.Gln36_Gln37dup	disruptive_inframe_insertion	Exon 1 of 67	NP_001375421.1	P42858
	HTT	NM_002111.8		c.105_110dupGCAGCA	p.Gln36_Gln37dup	disruptive_inframe_insertion	Exon 1 of 67	NP_002102.4	P42858

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
HTT	ENST00000355072.11	TSL:1 MANE Select	c.105_110dupGCAGCA	p.Gln36_Gln37dup	disruptive_inframe_insertion	Exon 1 of 67	ENSP00000347184.5	P42858
HTT	ENST00000681528.1		c.6-12009_6-12004dupGCAGCA		intron	N/A	ENSP00000506116.1	A0A7P0TAC5
HTT	ENST00000680956.1		c.6-12009_6-12004dupGCAGCA		intron	N/A	ENSP00000506029.1	A0A7P0TA78

Frequencies

GnomAD3 genomes

AF:

0.0389

AC:

5122

AN:

131756

Hom.:

121

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0453

Gnomad AMI

AF:

0.0138

Gnomad AMR

AF:

0.0394

Gnomad ASJ

AF:

0.0254

Gnomad EAS

AF:

0.0128

Gnomad SAS

AF:

0.0223

Gnomad FIN

AF:

0.0250

Gnomad MID

AF:

0.0224

Gnomad NFE

AF:

0.0406

Gnomad OTH

AF:

0.0390

GnomAD4 exome

AF:

0.0318

AC:

38958

AN:

1223798

Hom.:

2534

Cov.:

AF XY:

0.0322

AC XY:

19551

AN XY:

607118

show subpopulations

African (AFR)

AF:

0.0301

AC:

776

AN:

25786

American (AMR)

AF:

0.0306

AC:

926

AN:

30256

Ashkenazi Jewish (ASJ)

AF:

0.0224

AC:

509

AN:

22716

East Asian (EAS)

AF:

0.00928

AC:

270

AN:

29088

South Asian (SAS)

AF:

0.0277

AC:

2001

AN:

72150

European-Finnish (FIN)

AF:

0.0304

AC:

987

AN:

32484

Middle Eastern (MID)

AF:

0.0419

AC:

158

AN:

3774

European-Non Finnish (NFE)

AF:

0.0332

AC:

31724

AN:

955770

Other (OTH)

AF:

0.0310

AC:

1607

AN:

51774

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.460

Heterozygous variant carriers

1211

2421

3632

4842

6053

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1010

2020

3030

4040

5050

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0388

AC:

5117

AN:

131854

Hom.:

121

Cov.:

AF XY:

0.0382

AC XY:

2422

AN XY:

63406

show subpopulations

African (AFR)

AF:

0.0451

AC:

1603

AN:

35518

American (AMR)

AF:

0.0392

AC:

525

AN:

13406

Ashkenazi Jewish (ASJ)

AF:

0.0254

AC:

AN:

3190

East Asian (EAS)

AF:

0.0129

AC:

AN:

4120

South Asian (SAS)

AF:

0.0220

AC:

AN:

3908

European-Finnish (FIN)

AF:

0.0250

AC:

184

AN:

7368

Middle Eastern (MID)

AF:

0.0198

AC:

AN:

252

European-Non Finnish (NFE)

AF:

0.0406

AC:

2499

AN:

61476

Other (OTH)

AF:

0.0385

AC:

AN:

1816

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.532

Heterozygous variant carriers

216

432

648

864

1080

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

116

174

232

290

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0131

Hom.:

452

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

4.8

Mutation Taster

=80/20

polymorphism (auto)

(source)

Splicing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over