Genetic Variant NM_080683.3:c.661G>C (chr4-86701267-G-C) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_080683.3(PTPN13):c.661G>C(p.Asp221His) variant causes a missense change. The variant allele was found at a frequency of 0.000000694 in 1,441,386 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D221G) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

PTPN13
NM_080683.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.67

Publications

0 publications found

Variant links:

Genes affected

PTPN13 (HGNC:9646): (protein tyrosine phosphatase non-receptor type 13) The protein encoded by this gene is a member of the protein tyrosine phosphatase (PTP) family. PTPs are signaling molecules that regulate a variety of cellular processes including cell growth, differentiation, mitotic cycle, and oncogenic transformation. This PTP is a large intracellular protein. It has a catalytic PTP domain at its C-terminus and two major structural domains: a region with five PDZ domains and a FERM domain that binds to plasma membrane and cytoskeletal elements. This PTP was found to interact with, and dephosphorylate, Fas receptor and IkappaBalpha through the PDZ domains. This suggests it has a role in Fas mediated programmed cell death. This PTP was also shown to interact with GTPase-activating protein, and thus may function as a regulator of Rho signaling pathways. Four alternatively spliced transcript variants, which encode distinct proteins, have been reported. [provided by RefSeq, Oct 2008]

PTPN13 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.23466203).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PTPN13	NM_080683.3 link	c.661G>C	p.Asp221His	missense_variant	Exon 7 of 48	ENST00000411767.7	NP_542414.1	Q12923-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PTPN13	ENST00000411767.7 link	c.661G>C	p.Asp221His	missense_variant	Exon 7 of 48	1	NM_080683.3	ENSP00000407249.2		Q12923-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.94e-7

AC:

AN:

1441386

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

715504

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32338

American (AMR)

AF:

0.00

AC:

AN:

41032

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25024

East Asian (EAS)

AF:

0.00

AC:

AN:

39542

South Asian (SAS)

AF:

0.00

AC:

AN:

81912

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52834

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5630

European-Non Finnish (NFE)

AF:

9.06e-7

AC:

AN:

1103580

Other (OTH)

AF:

0.00

AC:

AN:

59494

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.625

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Aug 30, 2021

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.661G>C (p.D221H) alteration is located in exon 7 (coding exon 6) of the PTPN13 gene. This alteration results from a G to C substitution at nucleotide position 661, causing the aspartic acid (D) at amino acid position 221 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

0.15

BayesDel_addAF

Uncertain

0.044

BayesDel_noAF

Benign

-0.18

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.095

.;.;.;T;.

Eigen

Uncertain

0.66

Eigen_PC

Pathogenic

0.67

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.93

D;D;D;D;.

M_CAP

Benign

0.040

MetaRNN

Benign

0.23

T;T;T;T;T

MetaSVM

Benign

-0.84

MutationAssessor

Benign

2.0

M;M;M;M;M

PhyloP100

5.7

PrimateAI

Benign

0.47

PROVEAN

Benign

-2.1

N;N;N;N;N

REVEL

Benign

0.13

Sift

Uncertain

0.0010

D;D;D;D;D

Sift4G

Uncertain

0.0050

D;D;D;D;D

Polyphen

1.0

D;D;P;D;D

Vest4

0.41

MutPred

0.27

Gain of sheet (P = 0.0036);Gain of sheet (P = 0.0036);Gain of sheet (P = 0.0036);Gain of sheet (P = 0.0036);Gain of sheet (P = 0.0036);

MVP

0.51

MPC

0.25

ClinPred

0.94

GERP RS

5.5

Varity_R

0.23

gMVP

0.35

Mutation Taster

=66/34

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over