4-48086583-C-T

Variant names:

• chr4-48086583-C-T
• rs781683538
• NM_003328.3:c.839G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_003328.3(TXK):​c.839G>A​(p.Gly280Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G280C) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: TXK NM_003328.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.91
• Publications: 0 publications found

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]

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.989

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003328.3. 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
	TXK	NM_003328.3	MANE Select	c.839G>A	p.Gly280Asp	missense	Exon 10 of 15	NP_003319.2	P42681

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TXK	ENST00000264316.9	TSL:1 MANE Select	c.839G>A	p.Gly280Asp	missense	Exon 10 of 15	ENSP00000264316.4	P42681
	TXK	ENST00000506073.3	TSL:3	c.839G>A	p.Gly280Asp	missense	Exon 9 of 14	ENSP00000422798.2	E7EQN8
	TXK	ENST00000960124.1		c.839G>A	p.Gly280Asp	missense	Exon 10 of 13	ENSP00000630183.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.60	D
BayesDel_noAF	Pathogenic	0.62
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.91	D
Eigen	Pathogenic	0.97
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Uncertain	0.16	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.8	H
PhyloP100		7.9
PrimateAI	Pathogenic	0.81	D
PROVEAN	Pathogenic	-7.0	D
REVEL	Pathogenic	0.93
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.96
MutPred		0.95		Loss of glycosylation at S279 (P = 0.0607)
MVP		0.99
MPC		0.74
ClinPred		1.0	D
GERP RS		5.1
Varity_R		0.95
gMVP		0.82
Mutation Taster		=30/70	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs781683538; hg19: chr4-48088600;