rs1143646

Variant names:

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.3273T>G(p.Ile1091Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0483 in 1,613,944 control chromosomes in the GnomAD database, including 2,183 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.037 ( 158 hom., cov: 32)

Exomes 𝑓: 0.050 ( 2025 hom. )

Consequence

HTT
NM_001388492.1 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.427

Publications

14 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=0.001585871).

BP6

Variant 4-3146926-T-G is Benign according to our data. Variant chr4-3146926-T-G is described in ClinVar as Benign. ClinVar VariationId is 1651223.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0594 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HTT	NM_001388492.1 link	c.3273T>G	p.Ile1091Met	missense_variant	Exon 25 of 67	ENST00000355072.11	NP_001375421.1
HTT	NM_002111.8 link	c.3273T>G	p.Ile1091Met	missense_variant	Exon 25 of 67		NP_002102.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HTT	ENST00000355072.11 link	c.3273T>G	p.Ile1091Met	missense_variant	Exon 25 of 67	1	NM_001388492.1	ENSP00000347184.5

Frequencies

GnomAD3 genomes

AF:

0.0366

AC:

5574

AN:

152102

Hom.:

157

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00917

Gnomad AMI

AF:

0.204

Gnomad AMR

AF:

0.0323

Gnomad ASJ

AF:

0.0351

Gnomad EAS

AF:

0.000771

Gnomad SAS

AF:

0.0649

Gnomad FIN

AF:

0.0399

Gnomad MID

AF:

0.0443

Gnomad NFE

AF:

0.0525

Gnomad OTH

AF:

0.0325

GnomAD2 exomes

AF:

0.0401

AC:

9998

AN:

249570

AF XY:

0.0427

show subpopulations

Gnomad AFR exome

AF:

0.00859

Gnomad AMR exome

AF:

0.0207

Gnomad ASJ exome

AF:

0.0349

Gnomad EAS exome

AF:

0.000556

Gnomad FIN exome

AF:

0.0421

Gnomad NFE exome

AF:

0.0509

Gnomad OTH exome

AF:

0.0441

GnomAD4 exome

AF:

0.0495

AC:

72415

AN:

1461724

Hom.:

2025

Cov.:

AF XY:

0.0501

AC XY:

36413

AN XY:

727170

show subpopulations

African (AFR)

AF:

0.00744

AC:

249

AN:

33480

American (AMR)

AF:

0.0216

AC:

964

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0347

AC:

907

AN:

26136

East Asian (EAS)

AF:

0.000277

AC:

AN:

39700

South Asian (SAS)

AF:

0.0607

AC:

5233

AN:

86256

European-Finnish (FIN)

AF:

0.0425

AC:

2272

AN:

53420

Middle Eastern (MID)

AF:

0.0447

AC:

258

AN:

5766

European-Non Finnish (NFE)

AF:

0.0538

AC:

59817

AN:

1111850

Other (OTH)

AF:

0.0448

AC:

2704

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

3483

6966

10450

13933

17416

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2270

4540

6810

9080

11350

<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:

0.0366

AC:

5574

AN:

152220

Hom.:

158

Cov.:

AF XY:

0.0370

AC XY:

2750

AN XY:

74420

show subpopulations

African (AFR)

AF:

0.00915

AC:

380

AN:

41550

American (AMR)

AF:

0.0322

AC:

493

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.0351

AC:

122

AN:

3472

East Asian (EAS)

AF:

0.000772

AC:

AN:

5178

South Asian (SAS)

AF:

0.0654

AC:

315

AN:

4818

European-Finnish (FIN)

AF:

0.0399

AC:

422

AN:

10588

Middle Eastern (MID)

AF:

0.0374

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0525

AC:

3573

AN:

68004

Other (OTH)

AF:

0.0322

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

273

547

820

1094

1367

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

156

234

312

390

<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:

0.0450

Hom.:

628

Bravo

AF:

0.0339

TwinsUK

AF:

0.0593

AC:

220

ALSPAC

AF:

0.0581

AC:

224

ESP6500AA

AF:

0.00891

AC:

ESP6500EA

AF:

0.0484

AC:

403

ExAC

AF:

0.0397

AC:

4805

Asia WGS

AF:

0.0210

AC:

AN:

3478

EpiCase

AF:

0.0544

EpiControl

AF:

0.0509

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Jan 06, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.093

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.32

CADD

Benign

9.5

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.12

Eigen

Benign

-0.73

Eigen_PC

Benign

-0.82

FATHMM_MKL

Benign

0.36

LIST_S2

Benign

0.85

MetaRNN

Benign

0.0016

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.9

PhyloP100

-0.43

PrimateAI

Benign

0.45

PROVEAN

Benign

-0.32

REVEL

Benign

0.13

Sift

Uncertain

0.019

Sift4G

Uncertain

0.0020

Polyphen

0.49

Vest4

0.11

MPC

0.39

ClinPred

0.014

GERP RS

-4.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.10

gMVP

0.23

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

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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