Genetic Variant MATK:p.Gly399Arg (chr19-3778994-C-G) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_139355.3(MATK):c.1195G>C(p.Gly399Arg) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000713 in 1,403,302 control chromosomes in the GnomAD database, with no homozygous occurrence. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 7.1e-7 ( 0 hom. )

Consequence

MATK
NM_139355.3 missense, splice_region

Scores

Splicing: ADA: 0.003069

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.33

Publications

0 publications found

Variant links:

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]

MATK links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MATK	NM_139355.3	MANE Select	c.1195G>C	p.Gly399Arg	missense splice_region	Exon 12 of 14	NP_647612.1	P42679-1
MATK	NM_002378.4		c.1198G>C	p.Gly400Arg	missense splice_region	Exon 12 of 14	NP_002369.2
MATK	NM_001440577.1		c.1195G>C	p.Gly399Arg	missense splice_region	Exon 12 of 14	NP_001427506.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MATK	ENST00000310132.11	TSL:1 MANE Select	c.1195G>C	p.Gly399Arg	missense splice_region	Exon 12 of 14	ENSP00000308734.5	P42679-1
MATK	ENST00000585778.5	TSL:1	c.1195G>C	p.Gly399Arg	missense splice_region	Exon 12 of 14	ENSP00000468030.1	K7EQY5
MATK	ENST00000395040.6	TSL:1	c.1072G>C	p.Gly358Arg	missense splice_region	Exon 11 of 13	ENSP00000378481.1	P42679-3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.13e-7

AC:

AN:

1403302

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

693910

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31912

American (AMR)

AF:

0.00

AC:

AN:

37610

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23368

East Asian (EAS)

AF:

0.0000256

AC:

AN:

39124

South Asian (SAS)

AF:

0.00

AC:

AN:

81058

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40280

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5336

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1086608

Other (OTH)

AF:

0.00

AC:

AN:

58006

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.625

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.30

BayesDel_addAF

Benign

-0.052

BayesDel_noAF

Benign

-0.31

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.36

Eigen

Benign

0.059

Eigen_PC

Benign

0.085

FATHMM_MKL

Benign

0.58

LIST_S2

Uncertain

0.91

M_CAP

Uncertain

0.17

MetaRNN

Benign

0.39

MetaSVM

Benign

-0.65

MutationAssessor

Benign

0.49

PhyloP100

1.3

PrimateAI

Uncertain

0.63

PROVEAN

Benign

-1.7

REVEL

Uncertain

0.31

Sift

Benign

0.25

Sift4G

Uncertain

0.052

Polyphen

0.84

Vest4

0.26

MutPred

0.67

Gain of MoRF binding (P = 0.0289)

MVP

0.88

MPC

1.1

ClinPred

0.71

GERP RS

3.1

Varity_R

0.11

gMVP

0.55

Mutation Taster

=77/23

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0031

dbscSNV1_RF

Benign

0.020

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over