9-94097698-A-G

Position:

• chr9-94097698-A-G

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_001253829.2(PTPDC1):​c.1132A>G​(p.Met378Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000372 in 1,614,074 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: PTPDC1 NM_001253829.2 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 3.44

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 Likely_benign. Variant got -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.013931662).
• BP6: Variant 9-94097698-A-G is Benign according to our data. Variant chr9-94097698-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 2409067.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PTPDC1	NM_001253829.2	c.1132A>G	p.Met378Val	missense_variant	6/9	ENST00000620992.5
PTPDC1	NM_152422.4	c.1126A>G	p.Met376Val	missense_variant	6/9
PTPDC1	NM_177995.3	c.970A>G	p.Met324Val	missense_variant	7/10
PTPDC1	NM_001253830.2	c.970A>G	p.Met324Val	missense_variant	7/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PTPDC1	ENST00000620992.5	c.1132A>G	p.Met378Val	missense_variant	6/9	2	NM_001253829.2
PTPDC1	ENST00000288976.3	c.1126A>G	p.Met376Val	missense_variant	6/9	1
PTPDC1	ENST00000375360.7	c.970A>G	p.Met324Val	missense_variant	7/10	1		P1
PTPDC1	ENST00000650567.1	c.970A>G	p.Met324Val	missense_variant	8/11			P1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152186 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461888 Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3 AN XY: 727246

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152186 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74338

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 04, 2021

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.042
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.77
CADD	Benign	4.6
DANN	Benign	0.67
DEOGEN2	Benign	0.0097	T;T;T;.
Eigen	Benign	-0.99
Eigen_PC	Benign	-0.67
FATHMM_MKL	Benign	0.071	N
LIST_S2	Benign	0.61	.;T;T;T
M_CAP	Benign	0.0031	T
MetaRNN	Benign	0.014	T;T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	-1.6	N;N;.;.
MutationTaster	Benign	0.96	N;N
PrimateAI	Benign	0.29	T
PROVEAN	Benign	0.45	N;.;.;N
REVEL	Benign	0.098
Sift	Benign	1.0	T;.;.;T
Sift4G	Benign	1.0	T;.;T;T
Polyphen		0.0	B;B;.;B
Vest4		0.059
MutPred		0.11		Loss of methylation at K322 (P = 0.1402);Loss of methylation at K322 (P = 0.1402);.;.;
MVP		0.085
MPC		0.13
ClinPred		0.038	T
GERP RS		4.0
Varity_R		0.072
gMVP		0.30

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: rs997414673; hg19: chr9-96859980; COSMIC: COSV105860286; COSMIC: COSV105860286;