rs362331

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.6925T>C(p.Tyr2309His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.428 in 1,568,922 control chromosomes in the GnomAD database, including 146,149 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 0.47 ( 17425 hom., cov: 32)

Exomes 𝑓: 0.42 ( 128724 hom. )

Consequence

HTT
NM_001388492.1 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 3.22

Publications

76 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=1.4734268E-4).

BP6

Variant 4-3214108-T-C is Benign according to our data. Variant chr4-3214108-T-C is described in ClinVar as Benign. ClinVar VariationId is 1559386.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.579 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HTT	NM_001388492.1 link	c.6925T>C	p.Tyr2309His	missense_variant	Exon 50 of 67	ENST00000355072.11	NP_001375421.1
HTT	NM_002111.8 link	c.6925T>C	p.Tyr2309His	missense_variant	Exon 50 of 67		NP_002102.4	P42858

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HTT	ENST00000355072.11 link	c.6925T>C	p.Tyr2309His	missense_variant	Exon 50 of 67	1	NM_001388492.1	ENSP00000347184.5		P42858

Frequencies

GnomAD3 genomes

AF:

0.469

AC:

71325

AN:

151946

Hom.:

17389

Cov.:

show subpopulations

Gnomad AFR

AF:

0.585

Gnomad AMI

AF:

0.329

Gnomad AMR

AF:

0.383

Gnomad ASJ

AF:

0.506

Gnomad EAS

AF:

0.421

Gnomad SAS

AF:

0.306

Gnomad FIN

AF:

0.551

Gnomad MID

AF:

0.370

Gnomad NFE

AF:

0.423

Gnomad OTH

AF:

0.416

GnomAD2 exomes

AF:

0.429

AC:

97562

AN:

227262

AF XY:

0.421

show subpopulations

Gnomad AFR exome

AF:

0.582

Gnomad AMR exome

AF:

0.380

Gnomad ASJ exome

AF:

0.496

Gnomad EAS exome

AF:

0.430

Gnomad FIN exome

AF:

0.545

Gnomad NFE exome

AF:

0.424

Gnomad OTH exome

AF:

0.424

GnomAD4 exome

AF:

0.424

AC:

600684

AN:

1416858

Hom.:

128724

Cov.:

AF XY:

0.420

AC XY:

295062

AN XY:

702384

show subpopulations

African (AFR)

AF:

0.590

AC:

18857

AN:

31956

American (AMR)

AF:

0.376

AC:

15435

AN:

41082

Ashkenazi Jewish (ASJ)

AF:

0.502

AC:

12574

AN:

25058

East Asian (EAS)

AF:

0.414

AC:

15345

AN:

37100

South Asian (SAS)

AF:

0.309

AC:

25008

AN:

81046

European-Finnish (FIN)

AF:

0.537

AC:

28160

AN:

52416

Middle Eastern (MID)

AF:

0.389

AC:

2191

AN:

5630

European-Non Finnish (NFE)

AF:

0.422

AC:

458008

AN:

1084342

Other (OTH)

AF:

0.431

AC:

25106

AN:

58228

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

17406

34813

52219

69626

87032

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

14392

28784

43176

57568

71960

<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:

0.470

AC:

71410

AN:

152064

Hom.:

17425

Cov.:

AF XY:

0.467

AC XY:

34725

AN XY:

74360

show subpopulations

African (AFR)

AF:

0.585

AC:

24258

AN:

41460

American (AMR)

AF:

0.383

AC:

5858

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.506

AC:

1756

AN:

3470

East Asian (EAS)

AF:

0.420

AC:

2170

AN:

5166

South Asian (SAS)

AF:

0.305

AC:

1468

AN:

4816

European-Finnish (FIN)

AF:

0.551

AC:

5829

AN:

10578

Middle Eastern (MID)

AF:

0.381

AC:

112

AN:

294

European-Non Finnish (NFE)

AF:

0.423

AC:

28771

AN:

67970

Other (OTH)

AF:

0.421

AC:

889

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1890

3781

5671

7562

9452

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

628

1256

1884

2512

3140

<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:

0.434

Hom.:

49401

Bravo

AF:

0.464

TwinsUK

AF:

0.409

AC:

1518

ALSPAC

AF:

0.423

AC:

1629

ESP6500AA

AF:

0.565

AC:

2355

ESP6500EA

AF:

0.420

AC:

3533

ExAC

AF:

0.427

AC:

51670

Asia WGS

AF:

0.419

AC:

1458

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Feb 03, 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

0.059

BayesDel_addAF

Benign

-0.66

BayesDel_noAF

Benign

-0.58

CADD

Benign

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.11

Eigen

Benign

-0.61

Eigen_PC

Benign

-0.30

FATHMM_MKL

Benign

0.38

LIST_S2

Benign

0.12

MetaRNN

Benign

0.00015

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-1.5

PhyloP100

3.2

PrimateAI

Benign

0.45

PROVEAN

Benign

1.7

REVEL

Benign

0.18

Sift

Benign

0.69

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.026

MPC

0.49

ClinPred

0.0063

GERP RS

5.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Varity_R

0.026

gMVP

0.39

Mutation Taster

=96/4

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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