14-103405137-G-T

Variant names:

• chr14-103405137-G-T
• rs569205142
• NM_001128918.3:c.113G>T

Variant summary

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

The NM_001128918.3(MARK3):​c.113G>T​(p.Arg38Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,600 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R38Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: MARK3 NM_001128918.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.93
• Publications: 0 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)

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.113G>T	p.Arg38Leu	missense	Exon 2 of 18	NP_001122390.2	P27448-5
	MARK3	NM_001128919.3		c.113G>T	p.Arg38Leu	missense	Exon 2 of 17	NP_001122391.2	P27448-4
	MARK3	NM_001437366.1		c.113G>T	p.Arg38Leu	missense	Exon 2 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.113G>T	p.Arg38Leu	missense	Exon 2 of 18	ENSP00000411397.2	P27448-5
	MARK3	ENST00000556744.2	TSL:1	c.113G>T	p.Arg38Leu	missense	Exon 2 of 19	ENSP00000451623.2	H0YJI9
	MARK3	ENST00000416682.6	TSL:1	c.113G>T	p.Arg38Leu	missense	Exon 2 of 17	ENSP00000408092.2	P27448-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461600 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 727132

African (AFR) AF: 0.00 AC: 0 AN: 33446

American (AMR) AF: 0.00 AC: 0 AN: 44642

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26120

East Asian (EAS) AF: 0.00 AC: 0 AN: 39666

South Asian (SAS) AF: 0.00 AC: 0 AN: 86240

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111912

Other (OTH) AF: 0.0000166 AC: 1 AN: 60388

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.87
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.040
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.65	D
Eigen	Benign	0.11
Eigen_PC	Benign	0.090
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Uncertain	0.096	D
MetaRNN	Uncertain	0.72	D
MetaSVM	Uncertain	-0.15	T
MutationAssessor	Uncertain	2.8	M
PhyloP100		9.9
PrimateAI	Uncertain	0.64	T
PROVEAN	Uncertain	-4.1	D
REVEL	Uncertain	0.49
Sift	Benign	0.050	D
Sift4G	Uncertain	0.031	D
Polyphen		0.76	P
Vest4		0.75
MutPred		0.45		Gain of catalytic residue at R38 (P = 2e-04)
MVP		0.84
MPC		0.44
ClinPred		0.99	D
GERP RS		3.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.48
gMVP		0.50
Mutation Taster		=38/62	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: rs569205142; hg19: chr14-103871474;