4-86672517-C-G

Position:

• chr4-86672517-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_080683.3(PTPN13):​c.268C>G​(p.Leu90Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00111 in 1,606,290 control chromosomes in the GnomAD database, including 22 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0062 (13 hom., cov: 32)
  • Exomes 𝑓: 0.00058 (9 hom.)
• Consequence: PTPN13 NM_080683.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.41

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

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005671531).
• BP6: Variant 4-86672517-C-G is Benign according to our data. Variant chr4-86672517-C-G is described in ClinVar as [Benign]. Clinvar id is 708787.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00619 (943/152226) while in subpopulation AFR AF= 0.0213 (883/41534). AF 95% confidence interval is 0.0201. There are 13 homozygotes in gnomad4. There are 464 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 13 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PTPN13	NM_080683.3	c.268C>G	p.Leu90Val	missense_variant	3/48	ENST00000411767.7	NP_542414.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PTPN13	ENST00000411767.7	c.268C>G	p.Leu90Val	missense_variant	3/48	1	NM_080683.3	ENSP00000407249.2

Frequencies

GnomAD3 genomes AF: 0.00619 AC: 941 AN: 152108 Hom.: 13 Cov.: 32

Gnomad AFR AF: 0.0213

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00288

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: 0.0000441

Gnomad OTH AF: 0.00527

GnomAD3 exomes AF: 0.00150 AC: 354 AN: 236590 Hom.: 5 AF XY: 0.00126 AC XY: 161 AN XY: 127870

Gnomad AFR exome AF: 0.0222

Gnomad AMR exome AF: 0.00103

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000936

Gnomad OTH exome AF: 0.000346

GnomAD4 exome AF: 0.000578 AC: 840 AN: 1454064 Hom.: 9 Cov.: 31 AF XY: 0.000476 AC XY: 344 AN XY: 722440

Gnomad4 AFR exome AF: 0.0204

Gnomad4 AMR exome AF: 0.00124

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000118

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000153

Gnomad4 OTH exome AF: 0.00140

GnomAD4 genome AF: 0.00619 AC: 943 AN: 152226 Hom.: 13 Cov.: 32 AF XY: 0.00623 AC XY: 464 AN XY: 74438

Gnomad4 AFR AF: 0.0213

Gnomad4 AMR AF: 0.00288

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00521

Alfa AF: 0.00109 Hom.: 0

Bravo AF: 0.00733

ESP6500AA AF: 0.0183 AC: 67

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00178 AC: 215

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Benign	0.079	.;.;.;.;T;.;.
Eigen	Uncertain	0.29
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.95	D;D;D;D;D;T;.
MetaRNN	Benign	0.0057	T;T;T;T;T;T;T
MetaSVM	Benign	-1.2	T
MutationAssessor	Uncertain	2.4	M;M;.;M;M;.;M
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-0.91	N;N;N;N;N;N;N
REVEL	Benign	0.075
Sift	Benign	0.14	T;T;T;T;T;T;T
Sift4G	Uncertain	0.045	D;D;T;T;D;T;D
Polyphen		0.99	D;D;.;B;D;.;D
Vest4		0.20
MVP		0.34
MPC		0.23
ClinPred		0.034	T
GERP RS		5.5
Varity_R		0.13
gMVP		0.44

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs78046638; hg19: chr4-87593670; COSMIC: COSV57402870;