rs200166814

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBS1_SupportingBS2

The NM_001145026.2(PTPRQ):c.6586A>G(p.Met2196Val) variant causes a missense change. The variant allele was found at a frequency of 0.00202 in 1,549,064 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/16 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.0013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0021 ( 5 hom. )

Consequence

PTPRQ
NM_001145026.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4B:1

Conservation

PhyloP100: 6.85

Publications

1 publications found

Variant links:

Genes affected

PTPRQ (HGNC:9679): (protein tyrosine phosphatase receptor type Q) This locus encodes a member of the type III receptor-like protein-tyrosine phosphatase family. The encoded protein catalyzes the dephosphorylation of phosphotyrosine and phosphatidylinositol and plays roles in cellular proliferation and differentiation. Mutations at this locus have been linked to autosomal recessive deafness. [provided by RefSeq, Mar 2014]

PTPRQ Gene-Disease associations (from GenCC):

autosomal recessive nonsyndromic hearing loss 84A
Inheritance: AR, SD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae), PanelApp Australia
hearing loss, autosomal recessive
Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
hearing loss, autosomal dominant 73
Inheritance: AD, Unknown Classification: MODERATE, LIMITED Submitted by: PanelApp Australia, Ambry Genetics, Labcorp Genetics (formerly Invitae)
autosomal dominant nonsyndromic hearing loss
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

PTPRQ links:

ENSG00000304204 (HGNC:):

ENSG00000304204 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.02842471).

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00135 (205/152170) while in subpopulation NFE AF = 0.00249 (169/67976). AF 95% confidence interval is 0.00218. There are 0 homozygotes in GnomAd4. There are 92 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High Homozygotes in GnomAdExome4 at 5 AR,SD,AD,Unknown gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PTPRQ	NM_001145026.2 link	c.6586A>G	p.Met2196Val	missense_variant	Exon 42 of 45	ENST00000644991.3	NP_001138498.1
LOC105369867	XR_007063388.1 link	n.130+36633T>C		intron_variant	Intron 1 of 4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
PTPRQ	ENST00000644991.3 link	c.6586A>G	p.Met2196Val	missense_variant	Exon 42 of 45		NM_001145026.2	ENSP00000495607.1
PTPRQ	ENST00000616559.4 link	c.6685A>G	p.Met2229Val	missense_variant	Exon 42 of 45	5		ENSP00000483259.1
ENSG00000304204	ENST00000801015.1 link	n.100+36633T>C		intron_variant	Intron 1 of 2
ENSG00000304204	ENST00000801016.1 link	n.101-18125T>C		intron_variant	Intron 1 of 1

Frequencies

GnomAD3 genomes

AF:

0.00135

AC:

205

AN:

152052

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00105

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.000565

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00249

Gnomad OTH

AF:

0.000957

GnomAD2 exomes

AF:

0.00137

AC:

213

AN:

155238

AF XY:

0.00116

show subpopulations

Gnomad AFR exome

AF:

0.000248

Gnomad AMR exome

AF:

0.00177

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000296

Gnomad NFE exome

AF:

0.00219

Gnomad OTH exome

AF:

0.00481

GnomAD4 exome

AF:

0.00209

AC:

2917

AN:

1396894

Hom.:

Cov.:

AF XY:

0.00202

AC XY:

1392

AN XY:

688826

show subpopulations

African (AFR)

AF:

0.000350

AC:

AN:

31446

American (AMR)

AF:

0.00184

AC:

AN:

35314

Ashkenazi Jewish (ASJ)

AF:

0.0000398

AC:

AN:

25106

East Asian (EAS)

AF:

0.00

AC:

AN:

35634

South Asian (SAS)

AF:

0.000585

AC:

AN:

78598

European-Finnish (FIN)

AF:

0.000708

AC:

AN:

49402

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5688

European-Non Finnish (NFE)

AF:

0.00248

AC:

2671

AN:

1077682

Other (OTH)

AF:

0.00152

AC:

AN:

58024

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

165

329

494

658

823

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

108

216

324

432

540

<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:

0.00135

AC:

205

AN:

152170

Hom.:

Cov.:

AF XY:

0.00124

AC XY:

AN XY:

74410

show subpopulations

African (AFR)

AF:

0.000241

AC:

AN:

41534

American (AMR)

AF:

0.00105

AC:

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5160

South Asian (SAS)

AF:

0.000414

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.000565

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00249

AC:

169

AN:

67976

Other (OTH)

AF:

0.000947

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.511

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.00206

Hom.:

Bravo

AF:

0.00141

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00156

AC:

ESP6500AA

AF:

0.000723

AC:

ESP6500EA

AF:

0.00189

AC:

ExAC

AF:

0.00102

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4Benign:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Mar 06, 2017

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The M2196V variant in the PTPRQ gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The M2196V variant is observed in 19/9348 (0.2%) alleles from individuals of European background, in the ExAC dataset (Lek et al., 2016). The M2196V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position where amino acids with similar properties to Methionine are tolerated across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret M2196V as a variant of uncertain significance.

Breakthrough Genomics, Breakthrough Genomics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:not provided

Autosomal recessive nonsyndromic hearing loss 84A;C4540024:Hearing loss, autosomal dominant 73

Uncertain:1

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Hearing loss, autosomal recessive

Uncertain:1

Mar 07, 2022

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:research

PTPRQ-related disorder

Benign:1

Jan 05, 2023

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely 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

0.083

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.17

CADD

Benign

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.0024

T;.;.

Eigen

Benign

0.17

Eigen_PC

Uncertain

0.36

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.84

T;.;T

M_CAP

Benign

0.0034

MetaRNN

Benign

0.028

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.0

.;.;.

PhyloP100

6.8

PrimateAI

Uncertain

0.49

PROVEAN

Benign

0.0

.;.;.

REVEL

Benign

0.0

Sift

Pathogenic

0.0

.;.;.

Sift4G

Benign

0.16

T;T;.

Vest4

0.56

ClinPred

0.019

GERP RS

5.7

gMVP

0.25

Mutation Taster

=90/10

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

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

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