rs362272

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001388492.1(HTT):c.8356G>A(p.Val2786Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.293 in 1,610,054 control chromosomes in the GnomAD database, including 73,436 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.24 ( 5575 hom., cov: 34)

Exomes 𝑓: 0.30 ( 67861 hom. )

Consequence

HTT
NM_001388492.1 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 1.42

Publications

44 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0010347664).

BP6

Variant 4-3233253-G-A is Benign according to our data. Variant chr4-3233253-G-A is described in ClinVar as Benign. ClinVar VariationId is 1531045.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.344 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HTT	NM_001388492.1 link	c.8356G>A	p.Val2786Ile	missense_variant	Exon 61 of 67	ENST00000355072.11	NP_001375421.1
HTT	NM_002111.8 link	c.8356G>A	p.Val2786Ile	missense_variant	Exon 61 of 67		NP_002102.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HTT	ENST00000355072.11 link	c.8356G>A	p.Val2786Ile	missense_variant	Exon 61 of 67	1	NM_001388492.1	ENSP00000347184.5

Frequencies

GnomAD3 genomes

AF:

0.238

AC:

36286

AN:

152152

Hom.:

5571

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0584

Gnomad AMI

AF:

0.231

Gnomad AMR

AF:

0.250

Gnomad ASJ

AF:

0.297

Gnomad EAS

AF:

0.358

Gnomad SAS

AF:

0.200

Gnomad FIN

AF:

0.441

Gnomad MID

AF:

0.114

Gnomad NFE

AF:

0.307

Gnomad OTH

AF:

0.203

GnomAD2 exomes

AF:

0.287

AC:

71438

AN:

249088

AF XY:

0.283

show subpopulations

Gnomad AFR exome

AF:

0.0539

Gnomad AMR exome

AF:

0.292

Gnomad ASJ exome

AF:

0.287

Gnomad EAS exome

AF:

0.360

Gnomad FIN exome

AF:

0.437

Gnomad NFE exome

AF:

0.301

Gnomad OTH exome

AF:

0.283

GnomAD4 exome

AF:

0.299

AC:

436161

AN:

1457786

Hom.:

67861

Cov.:

AF XY:

0.296

AC XY:

214395

AN XY:

724564

show subpopulations

African (AFR)

AF:

0.0468

AC:

1567

AN:

33450

American (AMR)

AF:

0.283

AC:

12624

AN:

44674

Ashkenazi Jewish (ASJ)

AF:

0.289

AC:

7528

AN:

26090

East Asian (EAS)

AF:

0.344

AC:

13638

AN:

39602

South Asian (SAS)

AF:

0.196

AC:

16847

AN:

86144

European-Finnish (FIN)

AF:

0.427

AC:

22494

AN:

52638

Middle Eastern (MID)

AF:

0.118

AC:

680

AN:

5762

European-Non Finnish (NFE)

AF:

0.310

AC:

343907

AN:

1109284

Other (OTH)

AF:

0.281

AC:

16876

AN:

60142

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

15689

31379

47068

62758

78447

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

11298

22596

33894

45192

56490

<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:

0.238

AC:

36292

AN:

152268

Hom.:

5575

Cov.:

AF XY:

0.241

AC XY:

17933

AN XY:

74434

show subpopulations

African (AFR)

AF:

0.0582

AC:

2421

AN:

41576

American (AMR)

AF:

0.250

AC:

3822

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.297

AC:

1031

AN:

3472

East Asian (EAS)

AF:

0.358

AC:

1852

AN:

5174

South Asian (SAS)

AF:

0.199

AC:

962

AN:

4832

European-Finnish (FIN)

AF:

0.441

AC:

4679

AN:

10600

Middle Eastern (MID)

AF:

0.116

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.306

AC:

20837

AN:

67996

Other (OTH)

AF:

0.210

AC:

443

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

1362

2724

4087

5449

6811

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

384

768

1152

1536

1920

<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:

0.273

Hom.:

20181

Bravo

AF:

0.218

TwinsUK

AF:

0.307

AC:

1139

ALSPAC

AF:

0.310

AC:

1194

ESP6500AA

AF:

0.0672

AC:

285

ESP6500EA

AF:

0.296

AC:

2508

ExAC

AF:

0.279

AC:

33753

Asia WGS

AF:

0.301

AC:

1046

AN:

3478

EpiCase

AF:

0.293

EpiControl

AF:

0.286

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.067

BayesDel_addAF

Benign

-0.60

BayesDel_noAF

Benign

-0.49

CADD

Benign

0.060

(source)

DANN

Benign

0.75

DEOGEN2

Benign

0.11

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.28

LIST_S2

Benign

0.61

MetaRNN

Benign

0.0010

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.17

PhyloP100

1.4

PrimateAI

Benign

0.21

PROVEAN

Benign

0.070

REVEL

Benign

0.069

Sift

Benign

0.63

Sift4G

Benign

0.80

Polyphen

0.0020

Vest4

0.024

MPC

0.31

ClinPred

0.0030

GERP RS

-4.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.025

gMVP

0.041

Mutation Taster

=96/4

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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