1-214369591-G-C

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Moderate BP6_Moderate BS2

The NM_005401.5(PTPN14):c.3137C>G(p.Thr1046Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0016 in 1,614,154 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Synonymous variant affecting the same amino acid position (i.e. T1046T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0012 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0016 (5 hom.)
• Consequence: PTPN14 NM_005401.5 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 9.88

Genes affected

PTPN14 (HGNC:9647): (protein tyrosine phosphatase non-receptor type 14) 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 noncatalytic domain similar to that of band 4.1 superfamily cytoskeleton-associated proteins, which suggested the membrane or cytoskeleton localization of this protein. It appears to regulate lymphatic development in mammals, and a loss of function mutation has been found in a kindred with a lymphedema-choanal atresia. [provided by RefSeq, Sep 2010]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.076172054).
• BP6: Variant 1-214369591-G-C is Benign according to our data. Variant chr1-214369591-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 3025009.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAdExome at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PTPN14	NM_005401.5	c.3137C>G	p.Thr1046Arg	missense_variant	17/19	ENST00000366956.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PTPN14	ENST00000366956.10	c.3137C>G	p.Thr1046Arg	missense_variant	17/19	1	NM_005401.5	P1
PTPN14	ENST00000543945.5	c.*2413C>G		3_prime_UTR_variant	16/18	5

Frequencies

GnomAD3 genomes AF: 0.00118 AC: 179 AN: 152142 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000386

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000916

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00187

Gnomad OTH AF: 0.000958

GnomAD3 exomes AF: 0.00130 AC: 327 AN: 251490 Hom.: 2 AF XY: 0.00145 AC XY: 197 AN XY: 135920

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.000694

Gnomad ASJ exome AF: 0.00347

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00274

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.00149

Gnomad OTH exome AF: 0.00179

GnomAD4 exome AF: 0.00165 AC: 2408 AN: 1461894 Hom.: 5 Cov.: 36 AF XY: 0.00166 AC XY: 1209 AN XY: 727248

Gnomad4 AFR exome AF: 0.000269

Gnomad4 AMR exome AF: 0.000671

Gnomad4 ASJ exome AF: 0.00383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00268

Gnomad4 FIN exome AF: 0.0000562

Gnomad4 NFE exome AF: 0.00172

Gnomad4 OTH exome AF: 0.00176

GnomAD4 genome AF: 0.00118 AC: 179 AN: 152260 Hom.: 1 Cov.: 32 AF XY: 0.00120 AC XY: 89 AN XY: 74458

Gnomad4 AFR AF: 0.000385

Gnomad4 AMR AF: 0.000915

Gnomad4 ASJ AF: 0.00288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00187

Gnomad4 OTH AF: 0.000948

Alfa AF: 0.00105 Hom.: 0

Bravo AF: 0.00122

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.00182 AC: 7

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00174 AC: 15

ExAC AF: 0.00116 AC: 141

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00169

EpiControl AF: 0.00154

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

CeGaT Center for Human Genetics Tuebingen

Dec 01, 2023

PTPN14: PP3, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.46
BayesDel_addAF	Benign	0.010	T
BayesDel_noAF	Pathogenic	0.24
Cadd	Pathogenic	28
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.44	T
Eigen	Pathogenic	0.74
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.040	D
MetaRNN	Benign	0.076	T
MetaSVM	Uncertain	0.047	D
MutationAssessor	Benign	1.1	L
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.83	D
PROVEAN	Uncertain	-2.8	D
REVEL	Uncertain	0.58
Sift	Uncertain	0.0090	D
Sift4G	Uncertain	0.016	D
Polyphen		1.0	D
Vest4		0.79
MVP		0.87
MPC		1.1
ClinPred		0.064	T
GERP RS		5.5
Varity_R		0.81
gMVP		0.68

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: rs61749333; hg19: chr1-214542934; COSMIC: COSV65282096; COSMIC: COSV65282096;