19-3779009-C-A

Variant names:

• chr19-3779009-C-A
• rs1400666097
• NM_139355.3:c.1180G>T

Variant summary

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

The NM_139355.3(MATK):​c.1180G>T​(p.Glu394*) variant causes a stop gained change. The variant allele was found at a frequency of 0.000000704 in 1,420,468 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: MATK NM_139355.3 stop_gained
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.06
• 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: 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MATK	NM_139355.3	MANE Select	c.1180G>T	p.Glu394*	stop_gained	Exon 12 of 14	NP_647612.1	P42679-1
	MATK	NM_002378.4		c.1183G>T	p.Glu395*	stop_gained	Exon 12 of 14	NP_002369.2
	MATK	NM_001440577.1		c.1180G>T	p.Glu394*	stop_gained	Exon 12 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.1180G>T	p.Glu394*	stop_gained	Exon 12 of 14	ENSP00000308734.5	P42679-1
	MATK	ENST00000585778.5	TSL:1	c.1180G>T	p.Glu394*	stop_gained	Exon 12 of 14	ENSP00000468030.1	K7EQY5
	MATK	ENST00000395040.6	TSL:1	c.1057G>T	p.Glu353*	stop_gained	Exon 11 of 13	ENSP00000378481.1	P42679-3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.04e-7 AC: 1 AN: 1420468 Hom.: 0 Cov.: 32 AF XY: 0.00000142 AC XY: 1 AN XY: 703930

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 32392

American (AMR) AF: 0.00 AC: 0 AN: 40036

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24586

East Asian (EAS) AF: 0.00 AC: 0 AN: 39228

South Asian (SAS) AF: 0.00 AC: 0 AN: 83464

European-Finnish (FIN) AF: 0.0000236 AC: 1 AN: 42406

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5566

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1094100

Other (OTH) AF: 0.00 AC: 0 AN: 58690

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.61	D
BayesDel_noAF	Pathogenic	0.63
CADD	Pathogenic	43
DANN	Uncertain	1.0
Eigen	Pathogenic	0.91
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Uncertain	0.97	D
PhyloP100		6.1
Vest4		0.99
GERP RS		4.2
Mutation Taster		=10/190	disease causing (fs/PTC)

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: rs1400666097; hg19: chr19-3779007;