14-88479075-G-C

Variant summary

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

The NM_007039.4(PTPN21):c.2356C>G(p.Pro786Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000234 in 1,597,622 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0012 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00013 (0 hom.)
• Consequence: PTPN21 NM_007039.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.34

Genes affected

PTPN21 (HGNC:9651): (protein tyrosine phosphatase non-receptor type 21) The protein encoded by this gene is a member of the protein tyrosine phosphatase (PTP) family. PTPs are known to be signaling molecules that regulate a variety of cellular processes including cell growth, differentiation, mitotic cycle, and oncogenic transformation. This PTP contains an N-terminal domain, similar to cytoskeletal- associated proteins including band 4.1, ezrin, merlin, and radixin. This PTP was shown to specially interact with BMX/ETK, a member of Tec tyrosine kinase family characterized by a multimodular structures including PH, SH3, and SH2 domains. The interaction of this PTP with BMX kinase was found to increase the activation of STAT3, but not STAT2 kinase. Studies of the similar gene in mice suggested the possible roles of this PTP in liver regeneration and spermatogenesis. [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=0.005290836).
• BP6: Variant 14-88479075-G-C is Benign according to our data. Variant chr14-88479075-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 734851.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PTPN21	NM_007039.4	c.2356C>G	p.Pro786Ala	missense_variant	13/19	ENST00000556564.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PTPN21	ENST00000556564.6	c.2356C>G	p.Pro786Ala	missense_variant	13/19	1	NM_007039.4	P1
PTPN21	ENST00000328736.7	c.2356C>G	p.Pro786Ala	missense_variant	12/18	1		P1
PTPN21	ENST00000554270.5	n.2469C>G		non_coding_transcript_exon_variant	12/17	1
PTPN21	ENST00000536337.5	c.*2293C>G		3_prime_UTR_variant, NMD_transcript_variant	13/19	1

Frequencies

GnomAD3 genomes AF: 0.00125 AC: 191 AN: 152224 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00449

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000330 AC: 78 AN: 236008 Hom.: 0 AF XY: 0.000241 AC XY: 31 AN XY: 128578

Gnomad AFR exome AF: 0.00437

Gnomad AMR exome AF: 0.000283

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000581

Gnomad SAS exome AF: 0.0000348

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000927

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000127 AC: 184 AN: 1445280 Hom.: 0 Cov.: 31 AF XY: 0.000110 AC XY: 79 AN XY: 717914

Gnomad4 AFR exome AF: 0.00466

Gnomad4 AMR exome AF: 0.000260

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000473

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000634

Gnomad4 OTH exome AF: 0.000151

GnomAD4 genome AF: 0.00125 AC: 190 AN: 152342 Hom.: 1 Cov.: 32 AF XY: 0.00106 AC XY: 79 AN XY: 74490

Gnomad4 AFR AF: 0.00445

Gnomad4 AMR AF: 0.000261

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.0000674 Hom.: 0

Bravo AF: 0.00144

ESP6500AA AF: 0.00363 AC: 16

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000396 AC: 48

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Apr 04, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.52
Cadd	Benign	12
Dann	Benign	0.43
DEOGEN2	Benign	0.017	T;T
Eigen	Benign	-0.80
Eigen_PC	Benign	-0.72
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.75	T;.
M_CAP	Benign	0.030	D
MetaRNN	Benign	0.0053	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.97	L;L
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-1.4	N;N
REVEL	Benign	0.12
Sift	Benign	0.33	T;T
Sift4G	Benign	0.29	T;T
Polyphen		0.027	B;B
Vest4		0.24
MVP		0.71
MPC		0.31
ClinPred		0.0037	T
GERP RS		2.6
Varity_R		0.027

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: rs140596899; hg19: chr14-88945419;