9-36597242-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_014791.4(MELK):c.426A>C(p.Glu142Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: MELK NM_014791.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.947

Genes affected

MELK (HGNC:16870): (maternal embryonic leucine zipper kinase) Enables calcium ion binding activity; non-membrane spanning protein tyrosine kinase activity; and protein serine/threonine kinase activity. Involved in apoptotic process; cell population proliferation; and protein autophosphorylation. Located in cell cortex and plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3434535).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MELK	NM_014791.4	c.426A>C	p.Glu142Asp	missense_variant	6/18	ENST00000298048.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MELK	ENST00000298048.7	c.426A>C	p.Glu142Asp	missense_variant	6/18	1	NM_014791.4	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 27, 2022

The c.426A>C (p.E142D) alteration is located in exon 6 (coding exon 5) of the MELK gene. This alteration results from a A to C substitution at nucleotide position 426, causing the glutamic acid (E) at amino acid position 142 to be replaced by an aspartic acid (D). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	0.0032	T
BayesDel_noAF	Benign	-0.23
Cadd	Benign	17
Dann	Uncertain	0.99
DEOGEN2	Benign	0.039	T;.;.;.;.;.;T
Eigen	Benign	-0.17
Eigen_PC	Benign	-0.084
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.80	T;T;T;T;D;T;D
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.34	T;T;T;T;T;T;T
MetaSVM	Benign	-0.84	T
MutationAssessor	Benign	0.57	N;.;.;N;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-2.0	N;N;N;N;N;N;.
REVEL	Benign	0.23
Sift	Benign	0.15	T;T;T;T;T;T;.
Sift4G	Benign	0.18	T;T;T;T;T;T;T
Polyphen		0.34	B;.;.;.;.;.;.
Vest4		0.39
MutPred		0.37		Loss of ubiquitination at K145 (P = 0.2113);.;.;Loss of ubiquitination at K145 (P = 0.2113);.;.;.;
MVP		0.69
MPC		0.50
ClinPred		0.72	D
GERP RS		2.1
Varity_R		0.44
gMVP		0.50

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr9-36597239;