6-63578936-G-C

Variant names:

• chr6-63578936-G-C
• rs1778042801
• NM_003463.5:c.237G>C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_Strong PM2

The NM_001385268.2(PTP4A1):​c.199-1G>C variant causes a splice acceptor, intron change. The variant allele was found at a frequency of 0.000000691 in 1,447,104 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: PTP4A1 NM_001385268.2 splice_acceptor, intron
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.28

Genes affected

PTP4A1 (HGNC:9634): (protein tyrosine phosphatase 4A1) This gene encodes a member of a small class of prenylated protein tyrosine phosphatases (PTPs), which contain a PTP domain and a characteristic C-terminal prenylation motif. The encoded protein is a cell signaling molecule that plays regulatory roles in a variety of cellular processes, including cell proliferation and migration. The protein may also be involved in cancer development and metastasis. This tyrosine phosphatase is a nuclear protein, but may associate with plasma membrane by means of its prenylation motif. Pseudogenes related to this gene are located on chromosomes 1, 2, 5, 7, 11 and X. [provided by RefSeq, Jun 2013]

ENSG00000285976 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.1904762 fraction of the gene. Cryptic splice site detected, with MaxEntScore 8, offset of -39, new splice context is: taaatattcttctgacttAGgat. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PTP4A1	NM_003463.5	c.237G>C	p.Gln79His	missense_variant	Exon 4 of 6	ENST00000626021.3	NP_003454.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PTP4A1	ENST00000626021.3	c.237G>C	p.Gln79His	missense_variant	Exon 4 of 6	1	NM_003463.5	ENSP00000485687.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.91e-7 AC: 1 AN: 1447104 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 719792

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 9.03e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 15, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.237G>C (p.Q79H) alteration is located in exon 4 (coding exon 3) of the PTP4A1 gene. This alteration results from a G to C substitution at nucleotide position 237, causing the glutamine (Q) at amino acid position 79 to be replaced by a histidine (H). 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	0.26
BayesDel_addAF	Uncertain	0.088	D
BayesDel_noAF	Benign	-0.11
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.37	T;T;.
Eigen	Benign	-0.15
Eigen_PC	Benign	0.022
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.82	.;T;T
M_CAP	Benign	0.045	D
MetaRNN	Benign	0.37	T;T;T
MetaSVM	Benign	-0.65	T
MutationAssessor	Benign	1.4	L;L;.
PrimateAI	Uncertain	0.77	T
Sift4G	Benign	0.092	.;T;T
Polyphen		0.0080	B;B;.
Vest4		0.60, 0.59
MutPred		0.36		Gain of catalytic residue at D82 (P = 0.0645);Gain of catalytic residue at D82 (P = 0.0645);Gain of catalytic residue at D82 (P = 0.0645);
MVP		0.51
ClinPred		0.62	D
GERP RS		4.0
Varity_R		0.47
gMVP		0.72

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: rs1778042801; hg19: chr6-64288841;