Variant 4-48071520-A-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_003328.3(TXK):c.1512T>G(p.His504Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000508 in 1,612,894 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00029 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000026 ( 0 hom. )

Consequence

TXK
NM_003328.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.415

Variant links:

Genes affected

TXK (HGNC:12434): (TXK tyrosine kinase) Predicted to enable non-membrane spanning protein tyrosine kinase activity. Involved in positive regulation of interferon-gamma-mediated signaling pathway; positive regulation of macromolecule metabolic process; and protein autophosphorylation. Located in cytoplasm and nucleus. [provided by Alliance of Genome Resources, Apr 2022]

TXK links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.041148037).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TXK	NM_003328.3 linkuse as main transcript	c.1512T>G	p.His504Gln	missense_variant	14/15	ENST00000264316.9	NP_003319.2	P42681

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TXK	ENST00000264316.9 linkuse as main transcript	c.1512T>G	p.His504Gln	missense_variant	14/15	1	NM_003328.3	ENSP00000264316.4		P42681

Frequencies

GnomAD3 genomes

AF:

0.000289

AC:

AN:

152234

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00106

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.00

GnomAD3 exomes

AF:

0.0000600

AC:

AN:

249964

Hom.:

AF XY:

0.0000370

AC XY:

AN XY:

134976

show subpopulations

Gnomad AFR exome

AF:

0.000923

Gnomad AMR exome

AF:

0.00

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000260

AC:

AN:

1460542

Hom.:

Cov.:

AF XY:

0.0000151

AC XY:

AN XY:

726424

show subpopulations

Gnomad4 AFR exome

AF:

0.00108

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.000289

AC:

AN:

152352

Hom.:

Cov.:

AF XY:

0.000268

AC XY:

AN XY:

74494

show subpopulations

Gnomad4 AFR

AF:

0.00106

Gnomad4 AMR

AF:

0.00

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:

0.00

Alfa

AF:

0.000325

Hom.:

Bravo

AF:

0.000287

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000906

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 20, 2024

The c.1512T>G (p.H504Q) alteration is located in exon 14 (coding exon 14) of the TXK gene. This alteration results from a T to G substitution at nucleotide position 1512, causing the histidine (H) at amino acid position 504 to be replaced by a glutamine (Q). 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

0.22

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.37

CADD

Benign

DANN

Benign

0.88

DEOGEN2

Benign

0.38

T;.

Eigen

Benign

-0.95

Eigen_PC

Benign

-0.93

FATHMM_MKL

Benign

0.35

LIST_S2

Benign

0.68

T;T

M_CAP

Benign

0.060

MetaRNN

Benign

0.041

T;T

MetaSVM

Benign

-0.81

MutationAssessor

Benign

0.0050

N;.

PrimateAI

Uncertain

0.55

PROVEAN

Benign

-2.1

N;D

REVEL

Benign

0.21

Sift

Benign

0.27

T;T

Sift4G

Benign

0.26

T;T

Polyphen

0.79

P;.

Vest4

0.27

MutPred

0.33

Gain of ubiquitination at K506 (P = 0.0797);.;

MVP

0.73

MPC

0.65

ClinPred

0.033

GERP RS

-2.6

Varity_R

0.21

gMVP

0.50

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over