18-7567838-G-T

Position:

• chr18-7567838-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001105244.2(PTPRM):​c.20G>T​(p.Cys7Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000708 in 1,411,658 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: PTPRM NM_001105244.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.92

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.198699).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PTPRM	NM_001105244.2	c.20G>T	p.Cys7Phe	missense_variant	1/33	ENST00000580170.6	NP_001098714.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PTPRM	ENST00000580170.6	c.20G>T	p.Cys7Phe	missense_variant	1/33	1	NM_001105244.2	ENSP00000463325	A1
PTPRM	ENST00000332175.12	c.20G>T	p.Cys7Phe	missense_variant	1/31	1		ENSP00000331418	P4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.08e-7 AC: 1 AN: 1411658 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 701944

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000269

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 31, 2024

The c.20G>T (p.C7F) alteration is located in exon 1 (coding exon 1) of the PTPRM gene. This alteration results from a G to T substitution at nucleotide position 20, causing the cysteine (C) at amino acid position 7 to be replaced by a phenylalanine (F). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.051
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	22
DANN	Benign	0.97
DEOGEN2	Benign	0.30	.;T
Eigen	Benign	-0.26
Eigen_PC	Benign	-0.13
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.69	T;T
M_CAP	Uncertain	0.20	D
MetaRNN	Benign	0.20	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.34	N;N
MutationTaster	Benign	0.91	D;D;D
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-0.49	.;N
REVEL	Benign	0.062
Sift	Uncertain	0.0070	.;D
Sift4G	Uncertain	0.0090	D;D
Polyphen		0.0040	.;B
Vest4		0.28
MutPred		0.29		Loss of catalytic residue at L8 (P = 0.0182);Loss of catalytic residue at L8 (P = 0.0182);
MVP		0.13
MPC		0.89
ClinPred		0.83	D
GERP RS		3.5
Varity_R		0.30
gMVP		0.70

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: rs1007151692; hg19: chr18-7567836; COSMIC: COSV59860536;