14-103466359-G-A

Variant names:

• chr14-103466359-G-A
• rs1211526313
• NM_001128918.3:c.914G>A

Variant summary

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

The NM_001128918.3(MARK3):​c.914G>A​(p.Arg305Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,460,734 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: MARK3 NM_001128918.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.72
• Publications: 3 publications found

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]

MARK3 Gene-Disease associations (from GenCC):

• visual impairment and progressive phthisis bulbi

  Inheritance: Unknown, AR Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P

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_001128918.3. 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
	MARK3	NM_001128918.3	MANE Select	c.914G>A	p.Arg305Lys	missense	Exon 10 of 18	NP_001122390.2	P27448-5
	MARK3	NM_001128919.3		c.914G>A	p.Arg305Lys	missense	Exon 10 of 17	NP_001122391.2	P27448-4
	MARK3	NM_001437366.1		c.860G>A	p.Arg287Lys	missense	Exon 9 of 17	NP_001424295.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MARK3	ENST00000429436.7	TSL:1 MANE Select	c.914G>A	p.Arg305Lys	missense	Exon 10 of 18	ENSP00000411397.2	P27448-5
	MARK3	ENST00000556744.2	TSL:1	c.914G>A	p.Arg305Lys	missense	Exon 10 of 19	ENSP00000451623.2	H0YJI9
	MARK3	ENST00000416682.6	TSL:1	c.983G>A	p.Arg328Lys	missense	Exon 11 of 17	ENSP00000408092.2	P27448-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000803 AC: 2 AN: 248966 AF XY: 0.0000148

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000111

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1460734 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2 AN XY: 726714

African (AFR) AF: 0.00 AC: 0 AN: 33462

American (AMR) AF: 0.00 AC: 0 AN: 44616

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26114

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39670

South Asian (SAS) AF: 0.00 AC: 0 AN: 86190

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53406

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111162

Other (OTH) AF: 0.00 AC: 0 AN: 60348

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.16
CADD	Uncertain	25
DANN	Benign	0.79
DEOGEN2	Benign	0.22	T
Eigen	Benign	0.024
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.81	T
M_CAP	Benign	0.0090	T
MetaRNN	Uncertain	0.48	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.050	N
PhyloP100		9.7
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.17
Sift	Benign	0.88	T
Sift4G	Benign	1.0	T
Polyphen		0.028	B
Vest4		0.72
MutPred		0.53		Gain of catalytic residue at A309 (P = 0.0019)
MVP		0.51
MPC		0.84
ClinPred		0.31	T
GERP RS		5.5
Varity_R		0.88
gMVP		0.66
Mutation Taster		=28/72	disease causing

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: rs1211526313; hg19: chr14-103932696; COSMIC: COSV53507704; COSMIC: COSV53507704;