19-3778994-C-A

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_139355.3(MATK):c.1195G>T(p.Gly399Trp) 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 1,403,300 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. G399R) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 7.1e-7 ( 0 hom. )

Consequence

MATK
NM_139355.3 missense, splice_region

Scores

Splicing: ADA: 0.1141

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 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.792

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>T	p.Gly399Trp	missense splice_region	Exon 12 of 14	NP_647612.1	P42679-1
MATK	NM_002378.4		c.1198G>T	p.Gly400Trp	missense splice_region	Exon 12 of 14	NP_002369.2
MATK	NM_001440577.1		c.1195G>T	p.Gly399Trp	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>T	p.Gly399Trp	missense splice_region	Exon 12 of 14	ENSP00000308734.5	P42679-1
MATK	ENST00000585778.5	TSL:1	c.1195G>T	p.Gly399Trp	missense splice_region	Exon 12 of 14	ENSP00000468030.1	K7EQY5
MATK	ENST00000395040.6	TSL:1	c.1072G>T	p.Gly358Trp	missense splice_region	Exon 11 of 13	ENSP00000378481.1	P42679-3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.13e-7

AC:

AN:

1403300

Hom.:

Cov.:

AF XY:

0.00000144

AC XY:

AN XY:

693910

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31910

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

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.54

BayesDel_addAF

Uncertain

0.027

BayesDel_noAF

Benign

-0.20

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.86

Eigen

Uncertain

0.53

Eigen_PC

Uncertain

0.40

FATHMM_MKL

Benign

0.62

LIST_S2

Uncertain

0.92

M_CAP

Pathogenic

0.49

MetaRNN

Pathogenic

0.76

MetaSVM

Uncertain

-0.071

MutationAssessor

Uncertain

2.7

PhyloP100

1.3

PrimateAI

Uncertain

0.62

PROVEAN

Uncertain

-4.1

REVEL

Uncertain

0.41

Sift

Uncertain

0.0070

Sift4G

Uncertain

0.0050

Polyphen

1.0

Vest4

0.47

MutPred

0.68

Loss of disorder (P = 0.0129)

MVP

0.90

MPC

1.6

ClinPred

0.98

GERP RS

3.1

Varity_R

0.45

gMVP

0.61

Mutation Taster

=83/17

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.11

dbscSNV1_RF

Benign

0.55

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over