Genetic Variant NM_139355.3:c.1195G>C (chr19-3778994-C-G) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 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. 13/23 in silico tools predict a benign 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 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

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 made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MATK	NM_139355.3 link	c.1195G>C	p.Gly399Arg	missense_variant, splice_region_variant	Exon 12 of 14	ENST00000310132.11	NP_647612.1	P42679-1F1T0G6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MATK	ENST00000310132.11 link	c.1195G>C	p.Gly399Arg	missense_variant, splice_region_variant	Exon 12 of 14	1	NM_139355.3	ENSP00000308734.5		P42679-1

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

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000256

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.30

BayesDel_addAF

Benign

-0.052

BayesDel_noAF

Benign

-0.31

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.36

.;.;T;T;.

Eigen

Benign

0.059

Eigen_PC

Benign

0.085

FATHMM_MKL

Benign

0.58

LIST_S2

Uncertain

0.91

D;D;D;D;.

M_CAP

Uncertain

0.17

MetaRNN

Benign

0.39

T;T;T;T;T

MetaSVM

Benign

-0.65

MutationAssessor

Benign

0.49

.;.;N;.;.

PrimateAI

Uncertain

0.63

PROVEAN

Benign

-1.7

.;N;N;.;N

REVEL

Uncertain

0.31

Sift

Benign

0.25

.;T;T;.;T

Sift4G

Uncertain

0.052

T;D;D;T;T

Polyphen

0.84

.;.;P;.;.

Vest4

0.26

MutPred

0.67

.;.;Gain of MoRF binding (P = 0.0289);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

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over