NM_177977.3:c.1810G>A

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_177977.3(HAP1):c.1810G>A(p.Gly604Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00264 in 1,600,942 control chromosomes in the GnomAD database, including 81 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.014 ( 44 hom., cov: 33)

Exomes 𝑓: 0.0015 ( 37 hom. )

Consequence

HAP1
NM_177977.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.0900

Publications

4 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=0.0029521585).

BP6

Variant 17-41724751-C-T is Benign according to our data. Variant chr17-41724751-C-T is described in ClinVar as [Benign]. Clinvar id is 781300.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0135 (2061/152194) while in subpopulation AFR AF = 0.0464 (1929/41530). AF 95% confidence interval is 0.0447. There are 44 homozygotes in GnomAd4. There are 979 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 44 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HAP1	NM_177977.3 link	c.1810G>A	p.Gly604Arg	missense_variant	Exon 11 of 11	ENST00000347901.9	NP_817084.2	P54257-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HAP1	ENST00000347901.9 link	c.1810G>A	p.Gly604Arg	missense_variant	Exon 11 of 11	1	NM_177977.3	ENSP00000334002.4		P54257-2

Frequencies

GnomAD3 genomes

AF:

0.0135

AC:

2056

AN:

152076

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0464

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00537

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00116

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.000353

Gnomad OTH

AF:

0.00813

GnomAD2 exomes

AF:

0.00359

AC:

898

AN:

249840

AF XY:

0.00271

show subpopulations

Gnomad AFR exome

AF:

0.0452

Gnomad AMR exome

AF:

0.00252

Gnomad ASJ exome

AF:

0.0000998

Gnomad EAS exome

AF:

0.000598

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000414

Gnomad OTH exome

AF:

0.00245

GnomAD4 exome

AF:

0.00150

AC:

2173

AN:

1448748

Hom.:

Cov.:

AF XY:

0.00131

AC XY:

941

AN XY:

717750

show subpopulations

African (AFR)

AF:

0.0461

AC:

1533

AN:

33282

American (AMR)

AF:

0.00308

AC:

137

AN:

44520

Ashkenazi Jewish (ASJ)

AF:

0.0000769

AC:

AN:

26022

East Asian (EAS)

AF:

0.000280

AC:

AN:

39334

South Asian (SAS)

AF:

0.000325

AC:

AN:

86046

European-Finnish (FIN)

AF:

0.0000191

AC:

AN:

52408

Middle Eastern (MID)

AF:

0.00845

AC:

AN:

5444

European-Non Finnish (NFE)

AF:

0.000178

AC:

196

AN:

1101964

Other (OTH)

AF:

0.00367

AC:

219

AN:

59728

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

122

244

365

487

609

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0135

AC:

2061

AN:

152194

Hom.:

Cov.:

AF XY:

0.0132

AC XY:

979

AN XY:

74400

show subpopulations

African (AFR)

AF:

0.0464

AC:

1929

AN:

41530

American (AMR)

AF:

0.00536

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00116

AC:

AN:

5172

South Asian (SAS)

AF:

0.000415

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10600

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000353

AC:

AN:

67988

Other (OTH)

AF:

0.00805

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

103

207

310

414

517

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00543

Hom.:

Bravo

AF:

0.0148

ESP6500AA

AF:

0.0420

AC:

185

ESP6500EA

AF:

0.000581

AC:

ExAC

AF:

0.00429

AC:

521

Asia WGS

AF:

0.00722

AC:

AN:

3478

EpiCase

AF:

0.000709

EpiControl

AF:

0.000830

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

- -

Apr 30, 2018

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

0.14

BayesDel_addAF

Benign

-0.76

BayesDel_noAF

Benign

-0.83

CADD

Benign

4.4

(source)

DANN

Benign

0.63

DEOGEN2

Benign

0.090

.;.;.;T

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.019

LIST_S2

Benign

0.56

T;T;T;T

MetaRNN

Benign

0.0030

T;T;T;T

MetaSVM

Benign

-0.94

MutationAssessor

Benign

0.46

.;.;.;N

PhyloP100

-0.090

PrimateAI

Benign

0.38

PROVEAN

Benign

-2.3

N;D;N;D

REVEL

Benign

0.020

Sift

Benign

0.46

T;T;T;T

Sift4G

Benign

0.76

T;T;T;T

Polyphen

0.059

B;B;B;B

Vest4

0.093

MutPred

0.27

.;.;.;Gain of MoRF binding (P = 0.0031);

MVP

0.26

MPC

0.56

ClinPred

0.011

GERP RS

-2.4

PromoterAI

-0.0018

Neutral

(source)

Varity_R

0.045

gMVP

0.016

Mutation Taster

=99/1

polymorphism

(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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NM_177977.3:c.1810G>A

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