18-7774192-T-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BA1

The NM_001105244.2(PTPRM):c.117T>A(p.Ser39Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00399 in 1,612,842 control chromosomes in the GnomAD database, including 192 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.020 (93 hom., cov: 33)
  • Exomes 𝑓: 0.0024 (99 hom.)
• Consequence: PTPRM NM_001105244.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.21

Genes affected

PTPRM (HGNC:9675): (protein tyrosine phosphatase receptor type M) The protein encoded by this gene is a member of the protein tyrosine phosphatase (PTP) family. PTPs are known to be signaling molecules that regulate a variety of cellular processes including cell growth, differentiation, mitotic cycle, and oncogenic transformation. This PTP possesses an extracellular region, a single transmembrane region, and two tandem catalytic domains, and thus represents a receptor-type PTP. The extracellular region contains a meprin-A5 antigen-PTP mu (MAM) domain, an Ig-like domain and four fibronectin type III-like repeats. This PTP has been shown to mediate cell-cell aggregation through the interaction with another molecule of this PTP on an adjacent cell. This PTP can interact with scaffolding protein RACK1/GNB2L1, which may be necessary for the downstream signaling in response to cell-cell adhesion. Alternative splicing results in multiple transcripts encoding distinct isoforms. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• PP2: Missense variant where missense usually causes diseases, PTPRM
• BP4: Computational evidence support a benign effect (MetaRNN=0.00657779).
• BP6: Variant 18-7774192-T-A is Benign according to our data. Variant chr18-7774192-T-A is described in ClinVar as [Benign]. Clinvar id is 773336.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0651 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PTPRM	NM_001105244.2	c.117T>A	p.Ser39Arg	missense_variant	2/33	ENST00000580170.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PTPRM	ENST00000580170.6	c.117T>A	p.Ser39Arg	missense_variant	2/33	1	NM_001105244.2	A1
PTPRM	ENST00000332175.12	c.117T>A	p.Ser39Arg	missense_variant	2/31	1		P4
PTPRM	ENST00000400053.8	c.-70T>A		5_prime_UTR_variant	2/31	5
PTPRM	ENST00000400060.8	c.-3442T>A		5_prime_UTR_variant	1/32	5

Frequencies

GnomAD3 genomes AF: 0.0197 AC: 2992 AN: 152198 Hom.: 92 Cov.: 33

Gnomad AFR AF: 0.0672

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00850

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000558

Gnomad OTH AF: 0.0163

GnomAD3 exomes AF: 0.00564 AC: 1419 AN: 251418 Hom.: 53 AF XY: 0.00441 AC XY: 599 AN XY: 135880

Gnomad AFR exome AF: 0.0725

Gnomad AMR exome AF: 0.00390

Gnomad ASJ exome AF: 0.000992

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000392

Gnomad FIN exome AF: 0.000323

Gnomad NFE exome AF: 0.000466

Gnomad OTH exome AF: 0.00375

GnomAD4 exome AF: 0.00236 AC: 3443 AN: 1460526 Hom.: 99 Cov.: 31 AF XY: 0.00208 AC XY: 1508 AN XY: 726708

Gnomad4 AFR exome AF: 0.0751

Gnomad4 AMR exome AF: 0.00461

Gnomad4 ASJ exome AF: 0.000727

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000336

Gnomad4 FIN exome AF: 0.000318

Gnomad4 NFE exome AF: 0.000280

Gnomad4 OTH exome AF: 0.00495

GnomAD4 genome AF: 0.0197 AC: 3000 AN: 152316 Hom.: 93 Cov.: 33 AF XY: 0.0190 AC XY: 1417 AN XY: 74476

Gnomad4 AFR AF: 0.0672

Gnomad4 AMR AF: 0.00849

Gnomad4 ASJ AF: 0.000864

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.000559

Gnomad4 OTH AF: 0.0161

Alfa AF: 0.00346 Hom.: 13

Bravo AF: 0.0230

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0635 AC: 280

ESP6500EA AF: 0.000698 AC: 6

ExAC AF: 0.00628 AC: 763

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.000873

EpiControl AF: 0.000652

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

- -

PTPRM-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 17, 2020

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	Uncertain	0.35
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.22
Cadd	Benign	20
Dann	Uncertain	0.99
Eigen	Uncertain	0.22
Eigen_PC	Benign	0.20
FATHMM_MKL	Benign	0.76	D
LIST_S2	Benign	0.82	T;T
MetaRNN	Benign	0.0066	T;T
MetaSVM	Benign	-0.75	T
MutationAssessor	Benign	1.6	L;L
MutationTaster	Benign	0.97	D;D;D;D
PrimateAI	Uncertain	0.54	T
Sift4G	Benign	0.17	T;T
Polyphen		1.0	.;D
Vest4		0.64
MutPred		0.28		Gain of catalytic residue at S39 (P = 0.0576);Gain of catalytic residue at S39 (P = 0.0576);
MVP		0.75
MPC		1.1
ClinPred		0.028	T
GERP RS		1.6
Varity_R		0.64
gMVP		0.82

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: rs35224276; hg19: chr18-7774190; COSMIC: COSV59863360;