4-86764643-T-G

Variant names:

• chr4-86764643-T-G
• rs10033029
• NM_080683.3:c.4068T>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_080683.3(PTPN13):​c.4068T>G​(p.Phe1356Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.102 in 1,582,100 control chromosomes in the GnomAD database, including 9,112 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 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: 𝑓 0.084 (681 hom., cov: 32)
  • Exomes 𝑓: 0.10 (8431 hom.)
• Consequence: PTPN13 NM_080683.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.65
• Publications: 21 publications found

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]

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.001401037).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.111 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PTPN13	NM_080683.3	c.4068T>G	p.Phe1356Leu	missense_variant	Exon 25 of 48	ENST00000411767.7	NP_542414.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PTPN13	ENST00000411767.7	c.4068T>G	p.Phe1356Leu	missense_variant	Exon 25 of 48	1	NM_080683.3	ENSP00000407249.2

Frequencies

GnomAD3 genomes AF: 0.0837 AC: 12730 AN: 152156 Hom.: 679 Cov.: 32

Gnomad AFR AF: 0.0473

Gnomad AMI AF: 0.0636

Gnomad AMR AF: 0.0832

Gnomad ASJ AF: 0.115

Gnomad EAS AF: 0.0115

Gnomad SAS AF: 0.0488

Gnomad FIN AF: 0.0786

Gnomad MID AF: 0.0633

Gnomad NFE AF: 0.113

Gnomad OTH AF: 0.0927

GnomAD2 exomes AF: 0.0796 AC: 16891 AN: 212188 AF XY: 0.0812

Gnomad AFR exome AF: 0.0465

Gnomad AMR exome AF: 0.0472

Gnomad ASJ exome AF: 0.120

Gnomad EAS exome AF: 0.0126

Gnomad FIN exome AF: 0.0761

Gnomad NFE exome AF: 0.110

Gnomad OTH exome AF: 0.0895

GnomAD4 exome AF: 0.104 AC: 148426 AN: 1429826 Hom.: 8431 Cov.: 30 AF XY: 0.102 AC XY: 72587 AN XY: 709146

African (AFR) AF: 0.0449 AC: 1465 AN: 32592

American (AMR) AF: 0.0519 AC: 2035 AN: 39178

Ashkenazi Jewish (ASJ) AF: 0.122 AC: 3118 AN: 25502

East Asian (EAS) AF: 0.00876 AC: 338 AN: 38604

South Asian (SAS) AF: 0.0477 AC: 3833 AN: 80440

European-Finnish (FIN) AF: 0.0792 AC: 4155 AN: 52444

Middle Eastern (MID) AF: 0.0711 AC: 406 AN: 5708

European-Non Finnish (NFE) AF: 0.116 AC: 127158 AN: 1096088

Other (OTH) AF: 0.0998 AC: 5918 AN: 59270

GnomAD4 genome AF: 0.0836 AC: 12735 AN: 152274 Hom.: 681 Cov.: 32 AF XY: 0.0805 AC XY: 5993 AN XY: 74456

African (AFR) AF: 0.0474 AC: 1970 AN: 41578

American (AMR) AF: 0.0830 AC: 1269 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.115 AC: 400 AN: 3468

East Asian (EAS) AF: 0.0116 AC: 60 AN: 5186

South Asian (SAS) AF: 0.0486 AC: 235 AN: 4832

European-Finnish (FIN) AF: 0.0786 AC: 833 AN: 10600

Middle Eastern (MID) AF: 0.0646 AC: 19 AN: 294

European-Non Finnish (NFE) AF: 0.113 AC: 7697 AN: 68000

Other (OTH) AF: 0.0918 AC: 194 AN: 2114

Alfa AF: 0.103 Hom.: 2165

Bravo AF: 0.0838

TwinsUK AF: 0.122 AC: 454

ALSPAC AF: 0.116 AC: 447

ESP6500AA AF: 0.0534 AC: 192

ESP6500EA AF: 0.120 AC: 974

ExAC AF: 0.0757 AC: 9115

Asia WGS AF: 0.0340 AC: 121 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.45
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	19
DANN	Benign	0.86
DEOGEN2	Benign	0.0	.;.;.;T;.
Eigen	Benign	-0.57
Eigen_PC	Benign	-0.42
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.57	T;T;T;T;.
MetaRNN	Benign	0.0014	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	.;L;.;L;L
PhyloP100		2.6
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-0.89	N;N;N;N;N
REVEL	Benign	0.047
Sift	Benign	0.32	T;T;T;T;T
Sift4G	Benign	0.95	T;T;T;T;T
Vest4		0.046
ClinPred		0.0042	T
GERP RS		1.2
Varity_R		0.059
gMVP		0.20
Mutation Taster		=91/9	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs10033029; hg19: chr4-87685796; COSMIC: COSV57410377; COSMIC: COSV57410377;