14-103465639-A-G

Position:

• chr14-103465639-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The ENST00000429436.7(MARK3):​c.623A>G​(p.Lys208Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MARK3 ENST00000429436.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.32

Genes affected

MARK3 (HGNC:6897): (microtubule affinity regulating kinase 3) The protein encoded by this gene is activated by phosphorylation and in turn is involved in the phosphorylation of tau proteins MAP2 and MAP4. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2011]

ACMG classification

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/exons	MANE	Protein	UniProt
MARK3	NM_001128918.3	c.623A>G	p.Lys208Arg	missense_variant	8/18	ENST00000429436.7	NP_001122390.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MARK3	ENST00000429436.7	c.623A>G	p.Lys208Arg	missense_variant	8/18	1	NM_001128918.3	ENSP00000411397	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

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

Jun 10, 2024

The c.623A>G (p.K208R) alteration is located in exon 8 (coding exon 8) of the MARK3 gene. This alteration results from a A to G substitution at nucleotide position 623, causing the lysine (K) at amino acid position 208 to be replaced by an arginine (R). 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	0.18
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.40	.;T;.;.;.;.
Eigen	Uncertain	0.59
Eigen_PC	Pathogenic	0.66
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D;D;D;D;D;D
M_CAP	Benign	0.084	D
MetaRNN	Uncertain	0.56	D;D;D;D;D;D
MetaSVM	Benign	-0.44	T
MutationAssessor	Benign	0.71	.;N;N;N;N;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.87	D
PROVEAN	Uncertain	-2.8	D;D;D;D;D;D
REVEL	Uncertain	0.41
Sift	Uncertain	0.017	D;D;D;D;D;D
Sift4G	Benign	0.081	T;T;T;T;T;T
Polyphen		0.86	P;P;P;P;D;.
Vest4		0.56
MutPred		0.50		.;Gain of catalytic residue at D210 (P = 0);Gain of catalytic residue at D210 (P = 0);Gain of catalytic residue at D210 (P = 0);Gain of catalytic residue at D210 (P = 0);.;
MVP		0.73
MPC		2.5
ClinPred		0.98	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7
Varity_R		0.78
gMVP		0.56

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs2093488465; hg19: chr14-103931976;