9-94084751-C-T

Position:

• chr9-94084751-C-T

Variant summary

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

The NM_001253829.2(PTPDC1):​c.221C>T​(p.Thr74Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000028 in 1,427,480 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: PTPDC1 NM_001253829.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.77

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=0.15288258).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PTPDC1	NM_001253829.2	c.221C>T	p.Thr74Ile	missense_variant	1/9	ENST00000620992.5	NP_001240758.1
PTPDC1	NM_152422.4	c.221C>T	p.Thr74Ile	missense_variant	1/9		NP_689635.3
PTPDC1	NM_177995.3	c.83-500C>T		intron_variant			NP_818931.1
PTPDC1	NM_001253830.2	c.83-500C>T		intron_variant			NP_001240759.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PTPDC1	ENST00000620992.5	c.221C>T	p.Thr74Ile	missense_variant	1/9	2	NM_001253829.2	ENSP00000477817.1
PTPDC1	ENST00000288976.3	c.221C>T	p.Thr74Ile	missense_variant	1/9	1		ENSP00000288976.3
PTPDC1	ENST00000375360.7	c.83-500C>T		intron_variant		1		ENSP00000364509.3
PTPDC1	ENST00000650567.1	c.83-500C>T		intron_variant				ENSP00000497158.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000280 AC: 4 AN: 1427480 Hom.: 0 Cov.: 30 AF XY: 0.00000424 AC XY: 3 AN XY: 708030

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: 0.00000273

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

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 26, 2024

The c.221C>T (p.T74I) alteration is located in exon 1 (coding exon 1) of the PTPDC1 gene. This alteration results from a C to T substitution at nucleotide position 221, causing the threonine (T) at amino acid position 74 to be replaced by an isoleucine (I). 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
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0065	T;.
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.092
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.67	T;T
M_CAP	Benign	0.0096	T
MetaRNN	Benign	0.15	T;T
MetaSVM	Benign	-1.0	T
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.25	.;N
REVEL	Benign	0.042
Sift	Uncertain	0.0020	.;D
Sift4G	Benign	0.11	T;T
Polyphen		0.091	.;B
Vest4		0.27
MutPred		0.16		Gain of catalytic residue at P76 (P = 0.0309);Gain of catalytic residue at P76 (P = 0.0309);
MVP		0.35
MPC		0.15
ClinPred		0.98	D
GERP RS		4.8
gMVP		0.56

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		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: rs1356761508; hg19: chr9-96847033;