chr9-94095326-A-G

Position:

• chr9-94095326-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001253829.2(PTPDC1):​c.626A>G​(p.Tyr209Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000025 in 1,599,354 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: PTPDC1 NM_001253829.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.66

Genes affected

PTPDC1 (HGNC:30184): (protein tyrosine phosphatase domain containing 1) The protein encoded by this gene contains a characteristic motif of protein tyrosine phosphatases (PTPs). PTPs regulate activities of phosphoproteins through dephosphorylation. They are signaling molecules involved in the regulation of a wide variety of biological processes. The specific function of this protein has not yet been determined. Alternatively spliced transcript variants encoding distinct isoforms have been identified. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.871

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PTPDC1	NM_001253829.2	c.626A>G	p.Tyr209Cys	missense_variant	5/9	ENST00000620992.5	NP_001240758.1
PTPDC1	NM_152422.4	c.620A>G	p.Tyr207Cys	missense_variant	5/9		NP_689635.3
PTPDC1	NM_177995.3	c.464A>G	p.Tyr155Cys	missense_variant	6/10		NP_818931.1
PTPDC1	NM_001253830.2	c.464A>G	p.Tyr155Cys	missense_variant	6/10		NP_001240759.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PTPDC1	ENST00000620992.5	c.626A>G	p.Tyr209Cys	missense_variant	5/9	2	NM_001253829.2	ENSP00000477817.1
PTPDC1	ENST00000288976.3	c.620A>G	p.Tyr207Cys	missense_variant	5/9	1		ENSP00000288976.3
PTPDC1	ENST00000375360.7	c.464A>G	p.Tyr155Cys	missense_variant	6/10	1		ENSP00000364509.3
PTPDC1	ENST00000650567.1	c.464A>G	p.Tyr155Cys	missense_variant	7/11			ENSP00000497158.1

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 151828 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000484

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1447526 Hom.: 0 Cov.: 30 AF XY: 0.00000278 AC XY: 2 AN XY: 719784

Gnomad4 AFR exome AF: 0.0000306

Gnomad4 AMR exome AF: 0.0000244

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 AF: 0.0000132 AC: 2 AN: 151828 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74138

Gnomad4 AFR AF: 0.0000484

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000151

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

Sep 04, 2024

The c.620A>G (p.Y207C) alteration is located in exon 5 (coding exon 5) of the PTPDC1 gene. This alteration results from a A to G substitution at nucleotide position 620, causing the tyrosine (Y) at amino acid position 207 to be replaced by a cysteine (C). 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	Pathogenic	0.77
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.16
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.36	T;T;T;.
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.98	.;D;D;D
M_CAP	Benign	0.037	D
MetaRNN	Pathogenic	0.87	D;D;D;D
MetaSVM	Benign	-0.86	T
MutationAssessor	Pathogenic	3.1	M;M;.;.
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-7.6	D;.;.;D
REVEL	Pathogenic	0.69
Sift	Pathogenic	0.0	D;.;.;D
Sift4G	Pathogenic	0.0	D;.;D;D
Polyphen		1.0	D;D;.;D
Vest4		0.94
MutPred		0.70		Loss of stability (P = 0.0652);Loss of stability (P = 0.0652);.;.;
MVP		0.52
MPC		0.67
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.84
gMVP		0.90

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: rs1458090381; hg19: chr9-96857608;