4-3074876-CCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAG-CCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAG

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6BA1

The NM_001388492.1(HTT):c.108_110dupGCA(p.Gln37dup) variant causes a disruptive inframe insertion change. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.059 ( 287 hom., cov: 0)

Exomes 𝑓: 0.060 ( 2892 hom. )

Failed GnomAD Quality Control

Consequence

HTT
NM_001388492.1 disruptive_inframe_insertion

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B: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 -9 ACMG points.

BP6

Variant 4-3074876-C-CCAG is Benign according to our data. Variant chr4-3074876-C-CCAG is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1301634.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0671 is higher than 0.05.

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.108_110dupGCA	p.Gln37dup	disruptive_inframe_insertion	Exon 1 of 67	NP_001375421.1	P42858
	HTT	NM_002111.8		c.108_110dupGCA	p.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.108_110dupGCA	p.Gln37dup	disruptive_inframe_insertion	Exon 1 of 67	ENSP00000347184.5	P42858
HTT	ENST00000681528.1		c.6-12006_6-12004dupGCA		intron	N/A	ENSP00000506116.1	A0A7P0TAC5
HTT	ENST00000680956.1		c.6-12006_6-12004dupGCA		intron	N/A	ENSP00000506029.1	A0A7P0TA78

Frequencies

GnomAD3 genomes

AF:

0.0586

AC:

7726

AN:

131746

Hom.:

287

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0495

Gnomad AMI

AF:

0.00625

Gnomad AMR

AF:

0.0523

Gnomad ASJ

AF:

0.0878

Gnomad EAS

AF:

0.0244

Gnomad SAS

AF:

0.0432

Gnomad FIN

AF:

0.0515

Gnomad MID

AF:

0.0485

Gnomad NFE

AF:

0.0688

Gnomad OTH

AF:

0.0535

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0597

AC:

73050

AN:

1223772

Hom.:

2892

Cov.:

AF XY:

0.0599

AC XY:

36343

AN XY:

607184

show subpopulations

African (AFR)

AF:

0.0417

AC:

1074

AN:

25784

American (AMR)

AF:

0.0427

AC:

1293

AN:

30246

Ashkenazi Jewish (ASJ)

AF:

0.0825

AC:

1875

AN:

22714

East Asian (EAS)

AF:

0.0229

AC:

667

AN:

29078

South Asian (SAS)

AF:

0.0494

AC:

3565

AN:

72118

European-Finnish (FIN)

AF:

0.0498

AC:

1617

AN:

32470

Middle Eastern (MID)

AF:

0.0559

AC:

211

AN:

3772

European-Non Finnish (NFE)

AF:

0.0625

AC:

59751

AN:

955840

Other (OTH)

AF:

0.0579

AC:

2997

AN:

51750

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

2431

4862

7294

9725

12156

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2072

4144

6216

8288

10360

<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:

0.0586

AC:

7726

AN:

131844

Hom.:

287

Cov.:

AF XY:

0.0562

AC XY:

3566

AN XY:

63402

show subpopulations

African (AFR)

AF:

0.0492

AC:

1748

AN:

35514

American (AMR)

AF:

0.0523

AC:

701

AN:

13408

Ashkenazi Jewish (ASJ)

AF:

0.0878

AC:

280

AN:

3188

East Asian (EAS)

AF:

0.0245

AC:

101

AN:

4124

South Asian (SAS)

AF:

0.0433

AC:

169

AN:

3906

European-Finnish (FIN)

AF:

0.0515

AC:

379

AN:

7362

Middle Eastern (MID)

AF:

0.0476

AC:

AN:

252

European-Non Finnish (NFE)

AF:

0.0688

AC:

4231

AN:

61474

Other (OTH)

AF:

0.0551

AC:

100

AN:

1816

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.526

Heterozygous variant carriers

308

615

923

1230

1538

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

168

252

336

420

<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:

0.0459

Hom.:

452

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Huntington disease (1)

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