chr9-94088147-A-G

Position:

• chr9-94088147-A-G

Variant summary

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

The NM_001253829.2(PTPDC1):​c.500A>G​(p.His167Arg) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000434 in 1,612,430 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict 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: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: PTPDC1 NM_001253829.2 missense, splice_region
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.83

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1314623).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PTPDC1	NM_001253829.2	c.500A>G	p.His167Arg	missense_variant, splice_region_variant	4/9	ENST00000620992.5
PTPDC1	NM_152422.4	c.494A>G	p.His165Arg	missense_variant, splice_region_variant	4/9
PTPDC1	NM_177995.3	c.338A>G	p.His113Arg	missense_variant, splice_region_variant	5/10
PTPDC1	NM_001253830.2	c.338A>G	p.His113Arg	missense_variant, splice_region_variant	5/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PTPDC1	ENST00000620992.5	c.500A>G	p.His167Arg	missense_variant, splice_region_variant	4/9	2	NM_001253829.2
PTPDC1	ENST00000288976.3	c.494A>G	p.His165Arg	missense_variant, splice_region_variant	4/9	1
PTPDC1	ENST00000375360.7	c.338A>G	p.His113Arg	missense_variant, splice_region_variant	5/10	1		P1
PTPDC1	ENST00000650567.1	c.338A>G	p.His113Arg	missense_variant, splice_region_variant	6/11			P1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152096 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1460334 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 726354

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: 0.0000350

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152096 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74304

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000192

Gnomad4 SAS AF: 0.000208

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

Aug 21, 2023

The c.494A>G (p.H165R) alteration is located in exon 4 (coding exon 4) of the PTPDC1 gene. This alteration results from a A to G substitution at nucleotide position 494, causing the histidine (H) at amino acid position 165 to be replaced by an arginine (R). 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	0.073
BayesDel_addAF	Benign	-0.073	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	17
DANN	Benign	0.94
DEOGEN2	Benign	0.017	T;T;T;.
Eigen	Benign	-0.20
Eigen_PC	Benign	-0.041
FATHMM_MKL	Benign	0.67	D
LIST_S2	Uncertain	0.93	.;D;D;D
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.13	T;T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.99	L;L;.;.
MutationTaster	Benign	0.98	N;N
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-1.2	N;.;.;N
REVEL	Benign	0.10
Sift	Benign	0.35	T;.;.;T
Sift4G	Benign	0.34	T;.;T;T
Polyphen		0.045	B;B;.;B
Vest4		0.24
MutPred		0.54		Loss of sheet (P = 0.007);Loss of sheet (P = 0.007);.;.;
MVP		0.71
MPC		0.16
ClinPred		0.23	T
GERP RS		3.6
Varity_R		0.053
gMVP		0.83

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: rs758549300; hg19: chr9-96850429;