rs4523977

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_177977.3(HAP1):c.1322C>T(p.Thr441Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.227 in 1,584,764 control chromosomes in the GnomAD database, including 43,780 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 (★★). Synonymous variant affecting the same amino acid position (i.e. T441T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.18 ( 3108 hom., cov: 31)

Exomes 𝑓: 0.23 ( 40672 hom. )

Consequence

HAP1
NM_177977.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -0.837

Publications

31 publications found

Variant links:

Genes affected

HAP1 (HGNC:4812): (huntingtin associated protein 1) Huntington's disease (HD), a neurodegenerative disorder characterized by loss of striatal neurons, is caused by an expansion of a polyglutamine tract in the HD protein huntingtin. This gene encodes a protein that interacts with huntingtin, with two cytoskeletal proteins (dynactin and pericentriolar autoantigen protein 1), and with a hepatocyte growth factor-regulated tyrosine kinase substrate. The interactions with cytoskeletal proteins and a kinase substrate suggest a role for this protein in vesicular trafficking or organelle transport. Several alternatively spliced transcript variants encoding different isoforms have been described for this gene. [provided by RefSeq, Jul 2008]

HAP1 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=0.0025745928).

BP6

Variant 17-41727098-G-A is Benign according to our data. Variant chr17-41727098-G-A is described in ClinVar as [Benign]. Clinvar id is 1242257.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.334 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HAP1	NM_177977.3 link	c.1322C>T	p.Thr441Met	missense_variant	Exon 9 of 11	ENST00000347901.9	NP_817084.2	P54257-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
HAP1	ENST00000347901.9 link	c.1322C>T	p.Thr441Met	missense_variant	Exon 9 of 11	1	NM_177977.3	ENSP00000334002.4	P54257-2
HAP1	ENST00000310778.5 link	c.1478C>T	p.Thr493Met	missense_variant	Exon 10 of 12	1		ENSP00000309392.5	P54257-1
HAP1	ENST00000393939.6 link	c.1247C>T	p.Thr416Met	missense_variant	Exon 8 of 10	1		ENSP00000377513.2	P54257-3
HAP1	ENST00000341193.9 link	c.1271C>T	p.Thr424Met	missense_variant	Exon 8 of 10	2		ENSP00000343170.5	P54257-4

Frequencies

GnomAD3 genomes

AF:

0.181

AC:

27475

AN:

151976

Hom.:

3106

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0422

Gnomad AMI

AF:

0.219

Gnomad AMR

AF:

0.212

Gnomad ASJ

AF:

0.250

Gnomad EAS

AF:

0.227

Gnomad SAS

AF:

0.347

Gnomad FIN

AF:

0.269

Gnomad MID

AF:

0.215

Gnomad NFE

AF:

0.225

Gnomad OTH

AF:

0.191

GnomAD2 exomes

AF:

0.233

AC:

53177

AN:

227954

AF XY:

0.241

show subpopulations

Gnomad AFR exome

AF:

0.0356

Gnomad AMR exome

AF:

0.238

Gnomad ASJ exome

AF:

0.251

Gnomad EAS exome

AF:

0.214

Gnomad FIN exome

AF:

0.268

Gnomad NFE exome

AF:

0.224

Gnomad OTH exome

AF:

0.233

GnomAD4 exome

AF:

0.232

AC:

332256

AN:

1432670

Hom.:

40672

Cov.:

AF XY:

0.236

AC XY:

168200

AN XY:

712494

show subpopulations

African (AFR)

AF:

0.0333

AC:

1108

AN:

33232

American (AMR)

AF:

0.230

AC:

9665

AN:

41952

Ashkenazi Jewish (ASJ)

AF:

0.252

AC:

6469

AN:

25662

East Asian (EAS)

AF:

0.259

AC:

10192

AN:

39330

South Asian (SAS)

AF:

0.340

AC:

28682

AN:

84328

European-Finnish (FIN)

AF:

0.268

AC:

13999

AN:

52302

Middle Eastern (MID)

AF:

0.220

AC:

1260

AN:

5726

European-Non Finnish (NFE)

AF:

0.227

AC:

247642

AN:

1090786

Other (OTH)

AF:

0.223

AC:

13239

AN:

59352

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.455

Heterozygous variant carriers

11056

22112

33167

44223

55279

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.181

AC:

27471

AN:

152094

Hom.:

3108

Cov.:

AF XY:

0.186

AC XY:

13811

AN XY:

74340

show subpopulations

African (AFR)

AF:

0.0421

AC:

1748

AN:

41532

American (AMR)

AF:

0.212

AC:

3233

AN:

15264

Ashkenazi Jewish (ASJ)

AF:

0.250

AC:

867

AN:

3464

East Asian (EAS)

AF:

0.228

AC:

1181

AN:

5170

South Asian (SAS)

AF:

0.347

AC:

1674

AN:

4818

European-Finnish (FIN)

AF:

0.269

AC:

2841

AN:

10574

Middle Eastern (MID)

AF:

0.218

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.225

AC:

15268

AN:

67966

Other (OTH)

AF:

0.189

AC:

397

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

1082

2164

3247

4329

5411

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.211

Hom.:

9326

Bravo

AF:

0.165

TwinsUK

AF:

0.223

AC:

828

ALSPAC

AF:

0.221

AC:

850

ESP6500AA

AF:

0.0440

AC:

194

ESP6500EA

AF:

0.220

AC:

1896

ExAC

AF:

0.218

AC:

26419

Asia WGS

AF:

0.252

AC:

877

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Jun 11, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 22698993, 18192679) -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

HAP1-related disorder

Benign:1

Oct 24, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.098

BayesDel_addAF

Benign

-0.82

BayesDel_noAF

Benign

-0.80

CADD

Benign

0.28

(source)

DANN

Benign

0.57

DEOGEN2

Benign

0.063

.;.;.;T

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.0089

LIST_S2

Benign

0.60

T;T;T;T

MetaRNN

Benign

0.0026

T;T;T;T

MetaSVM

Benign

-0.90

MutationAssessor

Benign

-0.14

.;.;.;N

PhyloP100

-0.84

PrimateAI

Benign

0.33

PROVEAN

Benign

-1.4

N;N;N;N

REVEL

Benign

0.012

Sift

Benign

0.65

T;T;T;T

Sift4G

Benign

0.31

T;T;T;T

Polyphen

0.44

B;B;B;B

Vest4

0.10

MPC

0.11

ClinPred

0.0010

GERP RS

-4.3

Varity_R

0.018

gMVP

0.046

Mutation Taster

=97/3

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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rs4523977

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