14-103386055-C-T

Variant names:

• chr14-103386055-C-T
• rs1413560652
• NM_001128918.3:c.26C>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001128918.3(MARK3):​c.26C>T​(p.Thr9Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,822 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: MARK3 NM_001128918.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.07
• Publications: 2 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: AR, Unknown Classification: LIMITED Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)

ENSG00000303357 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3781928).

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.26C>T	p.Thr9Met	missense	Exon 1 of 18	NP_001122390.2	P27448-5
	MARK3	NM_001128919.3		c.26C>T	p.Thr9Met	missense	Exon 1 of 17	NP_001122391.2	P27448-4
	MARK3	NM_001437366.1		c.26C>T	p.Thr9Met	missense	Exon 1 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.26C>T	p.Thr9Met	missense	Exon 1 of 18	ENSP00000411397.2	P27448-5
	MARK3	ENST00000556744.2	TSL:1	c.26C>T	p.Thr9Met	missense	Exon 1 of 19	ENSP00000451623.2	H0YJI9
	MARK3	ENST00000416682.6	TSL:1	c.26C>T	p.Thr9Met	missense	Exon 1 of 17	ENSP00000408092.2	P27448-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000401 AC: 1 AN: 249528 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461822 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 727220

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.0000224 AC: 1 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111946

Other (OTH) AF: 0.00 AC: 0 AN: 60392

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

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	Pathogenic	0.81
BayesDel_addAF	Benign	-0.047	T
BayesDel_noAF	Benign	-0.22
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.59	D
Eigen	Uncertain	0.30
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Benign	0.11	N
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.36	D
MetaRNN	Benign	0.38	T
MetaSVM	Uncertain	0.069	D
MutationAssessor	Uncertain	2.3	M
PhyloP100		2.1
PrimateAI	Pathogenic	0.87	D
PROVEAN	Uncertain	-2.8	D
REVEL	Benign	0.28
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.015	D
Polyphen		0.93	P
Vest4		0.44
MutPred		0.22		Gain of catalytic residue at R4 (P = 0.0056)
MVP		0.84
MPC		0.69
ClinPred		0.98	D
GERP RS		3.6
PromoterAI		0.00020	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.19
gMVP		0.43
Mutation Taster		=82/18	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1413560652; hg19: chr14-103852392;