rs145125577

Variant names:

• chr18-7888232-A-G
• rs145125577
• NM_001105244.2:c.323A>G

Variant summary

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

The NM_001105244.2(PTPRM):​c.323A>G​(p.Asn108Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PTPRM NM_001105244.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.83

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=0.096300185).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PTPRM	NM_001105244.2	c.323A>G	p.Asn108Ser	missense_variant	Exon 3 of 33	ENST00000580170.6	NP_001098714.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PTPRM	ENST00000580170.6	c.323A>G	p.Asn108Ser	missense_variant	Exon 3 of 33	1	NM_001105244.2	ENSP00000463325.1
PTPRM	ENST00000332175.12	c.323A>G	p.Asn108Ser	missense_variant	Exon 3 of 31	1		ENSP00000331418.8
PTPRM	ENST00000400053.8	c.137A>G	p.Asn46Ser	missense_variant	Exon 3 of 31	5		ENSP00000382927.4
PTPRM	ENST00000400060	c.-3236A>G		5_prime_UTR_variant	Exon 2 of 32	5		ENSP00000382933.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251342 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135818

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 05, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.323A>G (p.N108S) alteration is located in exon 3 (coding exon 3) of the PTPRM gene. This alteration results from a A to G substitution at nucleotide position 323, causing the asparagine (N) at amino acid position 108 to be replaced by a serine (S). 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	0.064
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.055	.;T;T
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.097
FATHMM_MKL	Benign	0.52	D
LIST_S2	Benign	0.72	T;T;T
M_CAP	Benign	0.0035	T
MetaRNN	Benign	0.096	T;T;T
MetaSVM	Benign	-0.81	T
MutationAssessor	Benign	-0.69	N;N;.
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-0.18	.;N;N
REVEL	Benign	0.093
Sift	Benign	0.082	.;T;T
Sift4G	Benign	0.14	T;T;T
Polyphen		0.0	.;B;.
Vest4		0.26
MVP		0.39
MPC		0.46
ClinPred		0.33	T
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.070
gMVP		0.27

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: rs145125577; hg19: chr18-7888230;