chr1-220650683-G-T

Position:

• chr1-220650683-G-T

Variant summary

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

The NM_018650.5(MARK1):​c.1534G>T​(p.Asp512Tyr) 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: MARK1 NM_018650.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.36

Genes affected

MARK1 (HGNC:6896): (microtubule affinity regulating kinase 1) Enables several functions, including ATP binding activity; phospholipid binding activity; and protein kinase activity. Involved in intracellular signal transduction and protein phosphorylation. Located in cytoplasm; dendrite; and plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

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
MARK1	NM_018650.5	c.1534G>T	p.Asp512Tyr	missense_variant	14/18	ENST00000366917.6	NP_061120.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MARK1	ENST00000366917.6	c.1534G>T	p.Asp512Tyr	missense_variant	14/18	1	NM_018650.5	ENSP00000355884	P3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

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

Apr 18, 2023

The c.1534G>T (p.D512Y) alteration is located in exon 14 (coding exon 14) of the MARK1 gene. This alteration results from a G to T substitution at nucleotide position 1534, causing the aspartic acid (D) at amino acid position 512 to be replaced by a tyrosine (Y). 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	Uncertain	0.52
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.093	T;.;.;T
Eigen	Uncertain	0.68
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.97	D;D;D;D
M_CAP	Benign	0.012	T
MetaRNN	Uncertain	0.59	D;D;D;D
MetaSVM	Benign	-0.58	T
MutationAssessor	Uncertain	2.4	.;.;.;M
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.69	T
PROVEAN	Uncertain	-3.8	.;.;D;D
REVEL	Uncertain	0.36
Sift	Uncertain	0.0050	.;.;D;D
Sift4G	Uncertain	0.027	D;D;D;D
Polyphen		0.91, 0.98, 0.43	.;P;D;B
Vest4		0.68
MutPred		0.42		Gain of MoRF binding (P = 0.0438);Gain of MoRF binding (P = 0.0438);.;Gain of MoRF binding (P = 0.0438);
MVP		0.57
MPC		0.39
ClinPred		0.98	D
GERP RS		5.5
Varity_R		0.56
gMVP		0.57

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: chr1-220824025;