11-18740677-C-T

Position:

• chr11-18740677-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_006906.2(PTPN5):​c.841G>A​(p.Ala281Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000481 in 1,455,690 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: PTPN5 NM_006906.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.77

Genes affected

PTPN5 (HGNC:9657): (protein tyrosine phosphatase non-receptor type 5) Enables phosphotyrosine residue binding activity. Predicted to be involved in peptidyl-tyrosine dephosphorylation. Predicted to act upstream of or within protein dephosphorylation. Predicted to be located in nucleoplasm. Predicted to be integral component of membrane. Biomarker of Alzheimer's disease. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PTPN5	NM_006906.2	c.841G>A	p.Ala281Thr	missense_variant	8/15	ENST00000358540.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PTPN5	ENST00000358540.7	c.841G>A	p.Ala281Thr	missense_variant	8/15	1	NM_006906.2
PTPN5	ENST00000396168.1	c.769G>A	p.Ala257Thr	missense_variant	7/14	1		P1
PTPN5	ENST00000396170.5	c.745G>A	p.Ala249Thr	missense_variant	8/15	2
PTPN5	ENST00000477854.5	c.253G>A	p.Ala85Thr	missense_variant	4/11	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000481 AC: 7 AN: 1455690 Hom.: 0 Cov.: 30 AF XY: 0.00000414 AC XY: 3 AN XY: 723840

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000255

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000451

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 27, 2023

The c.841G>A (p.A281T) alteration is located in exon 8 (coding exon 7) of the PTPN5 gene. This alteration results from a G to A substitution at nucleotide position 841, causing the alanine (A) at amino acid position 281 to be replaced by a threonine (T). 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	0.34
BayesDel_addAF	Benign	-0.082	T
BayesDel_noAF	Benign	-0.36
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.34	.;T;.;.
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.82	T;T;T;T
M_CAP	Benign	0.026	D
MetaRNN	Uncertain	0.56	D;D;D;D
MetaSVM	Benign	-0.88	T
MutationAssessor	Uncertain	2.4	.;M;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Uncertain	0.61	T
PROVEAN	Uncertain	-3.1	D;D;D;D
REVEL	Benign	0.15
Sift	Uncertain	0.0090	D;D;D;D
Sift4G	Uncertain	0.038	D;D;D;D
Polyphen		0.99	.;D;.;.
Vest4		0.58
MutPred		0.37		.;Loss of helix (P = 0.0093);.;.;
MVP		0.61
MPC		0.97
ClinPred		1.0	D
GERP RS		5.1
Varity_R		0.34
gMVP		0.73

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: rs1849321988; hg19: chr11-18762224;