rs363075

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.2677G>A(p.Gly893Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0526 in 1,603,158 control chromosomes in the GnomAD database, including 2,493 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.041 ( 168 hom., cov: 32)

Exomes 𝑓: 0.054 ( 2325 hom. )

Consequence

HTT
NM_001388492.1 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 5.74

Publications

23 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=0.002583623).

BP6

Variant 4-3135947-G-A is Benign according to our data. Variant chr4-3135947-G-A is described in ClinVar as Benign. ClinVar VariationId is 1615277.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0589 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HTT	NM_001388492.1 link	c.2677G>A	p.Gly893Arg	missense_variant	Exon 20 of 67	ENST00000355072.11	NP_001375421.1
HTT	NM_002111.8 link	c.2677G>A	p.Gly893Arg	missense_variant	Exon 20 of 67		NP_002102.4	P42858

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HTT	ENST00000355072.11 link	c.2677G>A	p.Gly893Arg	missense_variant	Exon 20 of 67	1	NM_001388492.1	ENSP00000347184.5		P42858

Frequencies

GnomAD3 genomes

AF:

0.0408

AC:

6210

AN:

152172

Hom.:

168

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0111

Gnomad AMI

AF:

0.0439

Gnomad AMR

AF:

0.0519

Gnomad ASJ

AF:

0.0323

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.0209

Gnomad FIN

AF:

0.0438

Gnomad MID

AF:

0.0538

Gnomad NFE

AF:

0.0604

Gnomad OTH

AF:

0.0530

GnomAD2 exomes

AF:

0.0414

AC:

9882

AN:

238800

AF XY:

0.0421

show subpopulations

Gnomad AFR exome

AF:

0.0120

Gnomad AMR exome

AF:

0.0365

Gnomad ASJ exome

AF:

0.0301

Gnomad EAS exome

AF:

0.0000583

Gnomad FIN exome

AF:

0.0407

Gnomad NFE exome

AF:

0.0603

Gnomad OTH exome

AF:

0.0479

GnomAD4 exome

AF:

0.0538

AC:

78062

AN:

1450868

Hom.:

2325

Cov.:

AF XY:

0.0528

AC XY:

38139

AN XY:

721730

show subpopulations

African (AFR)

AF:

0.00882

AC:

290

AN:

32866

American (AMR)

AF:

0.0376

AC:

1578

AN:

42008

Ashkenazi Jewish (ASJ)

AF:

0.0309

AC:

801

AN:

25920

East Asian (EAS)

AF:

0.000102

AC:

AN:

39294

South Asian (SAS)

AF:

0.0193

AC:

1618

AN:

83902

European-Finnish (FIN)

AF:

0.0404

AC:

2151

AN:

53304

Middle Eastern (MID)

AF:

0.0502

AC:

287

AN:

5722

European-Non Finnish (NFE)

AF:

0.0617

AC:

68356

AN:

1107892

Other (OTH)

AF:

0.0496

AC:

2977

AN:

59960

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

Heterozygous variant carriers

3115

6230

9345

12460

15575

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2484

4968

7452

9936

12420

<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:

0.0408

AC:

6211

AN:

152290

Hom.:

168

Cov.:

AF XY:

0.0393

AC XY:

2925

AN XY:

74466

show subpopulations

African (AFR)

AF:

0.0111

AC:

461

AN:

41570

American (AMR)

AF:

0.0518

AC:

792

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.0323

AC:

112

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5192

South Asian (SAS)

AF:

0.0207

AC:

100

AN:

4824

European-Finnish (FIN)

AF:

0.0438

AC:

465

AN:

10606

Middle Eastern (MID)

AF:

0.0612

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0604

AC:

4111

AN:

68010

Other (OTH)

AF:

0.0525

AC:

111

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

305

610

914

1219

1524

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

140

210

280

350

<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:

0.0535

Hom.:

737

Bravo

AF:

0.0403

TwinsUK

AF:

0.0615

AC:

228

ALSPAC

AF:

0.0612

AC:

236

ESP6500AA

AF:

0.0133

AC:

ESP6500EA

AF:

0.0600

AC:

492

ExAC

AF:

0.0425

AC:

5135

Asia WGS

AF:

0.0110

AC:

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

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jan 06, 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

Uncertain

0.37

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.38

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.51

Eigen

Uncertain

0.65

Eigen_PC

Uncertain

0.64

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.89

MetaRNN

Benign

0.0026

MetaSVM

Benign

-1.2

MutationAssessor

Benign

2.0

PhyloP100

5.7

PrimateAI

Uncertain

0.66

PROVEAN

Uncertain

-3.4

REVEL

Uncertain

0.30

Sift

Uncertain

0.0030

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.084

MutPred

0.43

Gain of solvent accessibility (P = 0.0171);

MPC

0.13

ClinPred

0.014

GERP RS

4.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.57

gMVP

0.64

Mutation Taster

=86/14

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.13

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