1-220652005-A-G

Position:

• chr1-220652005-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_018650.5(MARK1):​c.1591A>G​(p.Ser531Gly) variant causes a missense change. The variant allele was found at a frequency of 0.000000688 in 1,453,190 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: MARK1 NM_018650.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.67

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.19993356).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MARK1	NM_018650.5	c.1591A>G	p.Ser531Gly	missense_variant	15/18	ENST00000366917.6	NP_061120.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MARK1	ENST00000366917.6	c.1591A>G	p.Ser531Gly	missense_variant	15/18	1	NM_018650.5	ENSP00000355884	P3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.88e-7 AC: 1 AN: 1453190 Hom.: 0 Cov.: 30 AF XY: 0.00000139 AC XY: 1 AN XY: 722014

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.05e-7

Gnomad4 OTH exome AF: 0.00

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

Dec 27, 2023

The c.1591A>G (p.S531G) alteration is located in exon 15 (coding exon 15) of the MARK1 gene. This alteration results from a A to G substitution at nucleotide position 1591, causing the serine (S) at amino acid position 531 to be replaced by a glycine (G). 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	0.063
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	20
DANN	Benign	0.95
DEOGEN2	Benign	0.010	T;.;.;T
Eigen	Benign	-0.18
Eigen_PC	Benign	-0.0051
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.82	T;T;T;T
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.20	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.9	.;.;.;L
MutationTaster	Benign	0.64	D;D;D
PrimateAI	Benign	0.47	T
PROVEAN	Uncertain	-2.6	.;D;N;N
REVEL	Benign	0.090
Sift	Benign	0.045	.;D;T;T
Sift4G	Benign	0.36	T;T;T;T
Polyphen		0.0	.;B;B;B
Vest4		0.29
MutPred		0.15		Loss of phosphorylation at S531 (P = 0.0116);Loss of phosphorylation at S531 (P = 0.0116);.;Loss of phosphorylation at S531 (P = 0.0116);
MVP		0.43
MPC		0.19
ClinPred		0.83	D
GERP RS		6.0
Varity_R		0.090
gMVP		0.31

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs1484415589; hg19: chr1-220825347;