Genetic Variant HAP1:p.Pro521Pro (chr17-41724998-C-T) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6BP7BA1

The NM_177977.3(HAP1):c.1563G>A(p.Pro521Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0136 in 1,612,826 control chromosomes in the GnomAD database, including 447 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

Frequency

Genomes: 𝑓 0.033 ( 180 hom., cov: 32)

Exomes 𝑓: 0.012 ( 267 hom. )

Consequence

HAP1
NM_177977.3 synonymous

Scores

Clinical Significance

Benign no assertion criteria provided B:1

Conservation

PhyloP100: -1.92

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 -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.78).

BP6

Variant 17-41724998-C-T is Benign according to our data. Variant chr17-41724998-C-T is described in ClinVar as [Benign]. Clinvar id is 3037846.Status of the report is no_assertion_criteria_provided, 0 stars.

BP7

Synonymous conserved (PhyloP=-1.91 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0874 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HAP1	NM_177977.3 link	c.1563G>A	p.Pro521Pro	synonymous_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.1563G>A	p.Pro521Pro	synonymous_variant	Exon 11 of 11	1	NM_177977.3	ENSP00000334002.4		P54257-2

Frequencies

GnomAD3 genomes

AF:

0.0324

AC:

4925

AN:

152098

Hom.:

177

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0894

Gnomad AMI

AF:

0.00987

Gnomad AMR

AF:

0.0195

Gnomad ASJ

AF:

0.0455

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00166

Gnomad FIN

AF:

0.00433

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.00938

Gnomad OTH

AF:

0.0292

GnomAD2 exomes

AF:

0.0151

AC:

3771

AN:

250506

AF XY:

0.0134

show subpopulations

Gnomad AFR exome

AF:

0.0944

Gnomad AMR exome

AF:

0.0101

Gnomad ASJ exome

AF:

0.0439

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00289

Gnomad NFE exome

AF:

0.0110

Gnomad OTH exome

AF:

0.0121

GnomAD4 exome

AF:

0.0116

AC:

16945

AN:

1460610

Hom.:

267

Cov.:

AF XY:

0.0112

AC XY:

8120

AN XY:

726684

show subpopulations

African (AFR)

AF:

0.0915

AC:

3064

AN:

33476

American (AMR)

AF:

0.0117

AC:

521

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.0457

AC:

1194

AN:

26130

East Asian (EAS)

AF:

0.000126

AC:

AN:

39700

South Asian (SAS)

AF:

0.00189

AC:

163

AN:

86256

European-Finnish (FIN)

AF:

0.00385

AC:

201

AN:

52230

Middle Eastern (MID)

AF:

0.0184

AC:

106

AN:

5766

European-Non Finnish (NFE)

AF:

0.00967

AC:

10752

AN:

1111952

Other (OTH)

AF:

0.0156

AC:

939

AN:

60382

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.457

Heterozygous variant carriers

958

1915

2873

3830

4788

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0325

AC:

4949

AN:

152216

Hom.:

180

Cov.:

AF XY:

0.0308

AC XY:

2293

AN XY:

74430

show subpopulations

African (AFR)

AF:

0.0898

AC:

3726

AN:

41512

American (AMR)

AF:

0.0195

AC:

298

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.0455

AC:

158

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5178

South Asian (SAS)

AF:

0.00145

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.00433

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.0136

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00940

AC:

639

AN:

68006

Other (OTH)

AF:

0.0289

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

228

455

683

910

1138

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0210

Hom.:

Bravo

AF:

0.0369

Asia WGS

AF:

0.0120

AC:

AN:

3478

EpiCase

AF:

0.0109

EpiControl

AF:

0.0128

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

HAP1-related disorder

Benign:1

Feb 28, 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

BayesDel_noAF

Benign

-0.78

CADD

Benign

0.21

(source)

DANN

Benign

0.63

PhyloP100

-1.9

PromoterAI

0.012

Neutral

(source)

Mutation Taster

=100/0

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

17-41724998-C-T

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