rs762904558

Variant names:

• chr19-3778311-C-T
• rs762904558
• NM_139355.3:c.1396G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_139355.3(MATK):​c.1396G>A​(p.Ala466Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000019 in 1,575,276 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000018 (0 hom.)
• Consequence: MATK NM_139355.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.119
• Publications: 0 publications found

Genes affected

MATK (HGNC:6906): (megakaryocyte-associated tyrosine kinase) The protein encoded by this gene has amino acid sequence similarity to Csk tyrosine kinase and has the structural features of the CSK subfamily: SRC homology SH2 and SH3 domains, a catalytic domain, a unique N terminus, lack of myristylation signals, lack of a negative regulatory phosphorylation site, and lack of an autophosphorylation site. This protein is thought to play a significant role in the signal transduction of hematopoietic cells. It is able to phosphorylate and inactivate Src family kinases, and may play an inhibitory role in the control of T-cell proliferation. This protein might be involved in signaling in some cases of breast cancer. Three alternatively spliced transcript variants that encode different isoforms have been described for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.068493634).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_139355.3. 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
	MATK	NM_139355.3	MANE Select	c.1396G>A	p.Ala466Thr	missense	Exon 14 of 14	NP_647612.1	P42679-1
	MATK	NM_002378.4		c.1399G>A	p.Ala467Thr	missense	Exon 14 of 14	NP_002369.2
	MATK	NM_001440577.1		c.1396G>A	p.Ala466Thr	missense	Exon 14 of 14	NP_001427506.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MATK	ENST00000310132.11	TSL:1 MANE Select	c.1396G>A	p.Ala466Thr	missense	Exon 14 of 14	ENSP00000308734.5	P42679-1
	MATK	ENST00000585778.5	TSL:1	c.1393G>A	p.Ala465Thr	missense	Exon 14 of 14	ENSP00000468030.1	K7EQY5
	MATK	ENST00000395040.6	TSL:1	c.1273G>A	p.Ala425Thr	missense	Exon 13 of 13	ENSP00000378481.1	P42679-3

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152180 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000965

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

GnomAD2 exomes AF: 0.0000327 AC: 7 AN: 214032 AF XY: 0.0000170

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000196

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000123

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000183 AC: 26 AN: 1423096 Hom.: 0 Cov.: 31 AF XY: 0.0000184 AC XY: 13 AN XY: 705934

African (AFR) AF: 0.0000637 AC: 2 AN: 31398

American (AMR) AF: 0.000288 AC: 10 AN: 34712

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24122

East Asian (EAS) AF: 0.0000764 AC: 3 AN: 39288

South Asian (SAS) AF: 0.0000368 AC: 3 AN: 81632

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50650

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5588

European-Non Finnish (NFE) AF: 0.00000456 AC: 5 AN: 1097008

Other (OTH) AF: 0.0000511 AC: 3 AN: 58698

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152180 Hom.: 0 Cov.: 33 AF XY: 0.0000403 AC XY: 3 AN XY: 74352

African (AFR) AF: 0.0000965 AC: 4 AN: 41442

American (AMR) AF: 0.00 AC: 0 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68016

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000302

ExAC AF: 0.0000580 AC: 7

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	Benign	0.083
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	12
DANN	Benign	0.89
DEOGEN2	Benign	0.28	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.093	N
LIST_S2	Benign	0.62	T
M_CAP	Benign	0.040	D
MetaRNN	Benign	0.068	T
MetaSVM	Benign	-0.77	T
MutationAssessor	Benign	0.045	N
PhyloP100		0.12
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-0.82	N
REVEL	Benign	0.10
Sift	Benign	0.50	T
Sift4G	Benign	0.56	T
Polyphen		0.0020	B
Vest4		0.12
MVP		0.69
MPC		0.51
ClinPred		0.015	T
GERP RS		-1.5
Varity_R		0.054
gMVP		0.12
Mutation Taster		=95/5	polymorphism

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

Other links and lift over

dbSNP: rs762904558; hg19: chr19-3778309; COSMIC: COSV59554010; COSMIC: COSV59554010;