rs777342703

Variant names:

• chr14-88473723-C-G
• rs777342703
• NM_007039.4:c.2591G>C

Your query was ambiguous. Multiple possible variants found:

• chr14-88473723-C-G
• chr14-88473723-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_007039.4(PTPN21):​c.2591G>C​(p.Arg864Pro) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,460,226 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R864Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: PTPN21 NM_007039.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.84
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.8

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_007039.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PTPN21	NM_007039.4	MANE Select	c.2591G>C	p.Arg864Pro	missense	Exon 14 of 19	NP_008970.2	Q16825

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PTPN21	ENST00000556564.6	TSL:1 MANE Select	c.2591G>C	p.Arg864Pro	missense	Exon 14 of 19	ENSP00000452414.1	Q16825
	PTPN21	ENST00000328736.7	TSL:1	c.2591G>C	p.Arg864Pro	missense	Exon 13 of 18	ENSP00000330276.3	Q16825
	PTPN21	ENST00000536337.5	TSL:1	n.*2528G>C		non_coding_transcript_exon	Exon 14 of 19	ENSP00000443951.1	G3V1Q9

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460226 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726394

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33354

American (AMR) AF: 0.00 AC: 0 AN: 44214

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26098

East Asian (EAS) AF: 0.00 AC: 0 AN: 39654

South Asian (SAS) AF: 0.00 AC: 0 AN: 85744

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53396

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111676

Other (OTH) AF: 0.00 AC: 0 AN: 60326

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.37
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
CADD	Pathogenic	32
DANN	Uncertain	0.99
DEOGEN2	Benign	0.15	T
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	D
M_CAP	Uncertain	0.18	D
MetaRNN	Pathogenic	0.80	D
MetaSVM	Uncertain	-0.0099	T
MutationAssessor	Uncertain	2.7	M
PhyloP100		5.8
PrimateAI	Uncertain	0.57	T
PROVEAN	Uncertain	-3.4	D
REVEL	Uncertain	0.51
Sift	Uncertain	0.0030	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.87
MutPred		0.40		Loss of catalytic residue at R864 (P = 0.0866)
MVP		0.89
MPC		1.3
ClinPred		0.99	D
GERP RS		5.5
Varity_R		0.73
Mutation Taster		=52/48	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.45		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.45		Position offset: -3

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

Other links and lift over

dbSNP: rs777342703; hg19: chr14-88940067;