rs200166814

Positions:

• chr12-80670476-A-G

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

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. 10/14 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
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3 B:1
• Conservation: PhyloP100: 6.85

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]

LOC105369867 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAdExome4 at 5 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PTPRQ	NM_001145026.2	c.6586A>G	p.Met2196Val	missense_variant	42/45	ENST00000644991.3	NP_001138498.1
LOC105369867	XR_007063388.1	n.130+36633T>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PTPRQ	ENST00000644991.3	c.6586A>G	p.Met2196Val	missense_variant	42/45		NM_001145026.2	ENSP00000495607.1
PTPRQ	ENST00000616559.4	c.6685A>G	p.Met2229Val	missense_variant	42/45	5		ENSP00000483259.1

Frequencies

GnomAD3 genomes AF: 0.00135 AC: 205 AN: 152052 Hom.: 0 Cov.: 32

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

GnomAD3 exomes AF: 0.00137 AC: 213 AN: 155238 Hom.: 1 AF XY: 0.00116 AC XY: 95 AN XY: 81886

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 SAS exome AF: 0.000449

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.: 5 Cov.: 30 AF XY: 0.00202 AC XY: 1392 AN XY: 688826

Gnomad4 AFR exome AF: 0.000350

Gnomad4 AMR exome AF: 0.00184

Gnomad4 ASJ exome AF: 0.0000398

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000585

Gnomad4 FIN exome AF: 0.000708

Gnomad4 NFE exome AF: 0.00248

Gnomad4 OTH exome AF: 0.00152

GnomAD4 genome AF: 0.00135 AC: 205 AN: 152170 Hom.: 0 Cov.: 32 AF XY: 0.00124 AC XY: 92 AN XY: 74410

Gnomad4 AFR AF: 0.000241

Gnomad4 AMR AF: 0.00105

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.000565

Gnomad4 NFE AF: 0.00249

Gnomad4 OTH AF: 0.000947

Alfa AF: 0.00212 Hom.: 0

Bravo AF: 0.00141

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.000723 AC: 1

ESP6500EA AF: 0.00189 AC: 6

ExAC AF: 0.00102 AC: 26

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3 Benign:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Mar 06, 2017	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. -
Uncertain significance, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Autosomal recessive nonsyndromic hearing loss 84A;C4540024:Hearing loss, autosomal dominant 73 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

PTPRQ-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 05, 2023

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	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	23
DANN	Benign	0.95
DEOGEN2	Benign	0.0024	T;.;.
Eigen	Benign	0.17
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.84	T;.;T
M_CAP	Benign	0.0034	T
MetaRNN	Benign	0.028	T;T;T
MetaSVM	Benign	-1.1	T
PrimateAI	Uncertain	0.49	T
Sift4G	Benign	0.16	T;T;.
Vest4		0.56
MVP		0.17
ClinPred		0.019	T
GERP RS		5.7
gMVP		0.25

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

LitVar

Other links and lift over

dbSNP: rs200166814; hg19: chr12-81064255;