14-103468064-A-G

Variant names:

• chr14-103468064-A-G
• rs747903624
• NM_001128918.3:c.1142A>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001128918.3(MARK3):​c.1142A>G​(p.Asn381Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000124 in 1,613,814 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 30)
  • Exomes 𝑓: 0.000013 (0 hom.)
• Consequence: MARK3 NM_001128918.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.18
• 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: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.09306377).

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.1142A>G	p.Asn381Ser	missense	Exon 12 of 18	NP_001122390.2	P27448-5
	MARK3	NM_001128919.3		c.1142A>G	p.Asn381Ser	missense	Exon 12 of 17	NP_001122391.2	P27448-4
	MARK3	NM_001437366.1		c.1088A>G	p.Asn363Ser	missense	Exon 11 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.1142A>G	p.Asn381Ser	missense	Exon 12 of 18	ENSP00000411397.2	P27448-5
	MARK3	ENST00000416682.6	TSL:1	c.1211A>G	p.Asn404Ser	missense	Exon 13 of 17	ENSP00000408092.2	P27448-2
	MARK3	ENST00000553942.5	TSL:1	c.1142A>G	p.Asn381Ser	missense	Exon 12 of 17	ENSP00000450772.1	P27448-4

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152088 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000201 AC: 5 AN: 249326 AF XY: 0.00000739

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: 0.0000177

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.0000130 AC: 19 AN: 1461726 Hom.: 0 Cov.: 31 AF XY: 0.0000124 AC XY: 9 AN XY: 727162

African (AFR) AF: 0.00 AC: 0 AN: 33470

American (AMR) AF: 0.0000224 AC: 1 AN: 44692

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39692

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86222

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5768

European-Non Finnish (NFE) AF: 0.0000108 AC: 12 AN: 1111952

Other (OTH) AF: 0.0000166 AC: 1 AN: 60386

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 152088 Hom.: 0 Cov.: 30 AF XY: 0.0000135 AC XY: 1 AN XY: 74302

African (AFR) AF: 0.00 AC: 0 AN: 41416

American (AMR) AF: 0.00 AC: 0 AN: 15244

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68024

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.0000414 AC: 5

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

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	0.075
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	21
DANN	Benign	0.19
DEOGEN2	Benign	0.26	T
Eigen	Benign	-0.53
Eigen_PC	Benign	-0.33
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.0090	T
MetaRNN	Benign	0.093	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.99	L
PhyloP100		6.2
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.052
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0010	B
Vest4		0.33
MutPred		0.35		Gain of phosphorylation at N381 (P = 0.0025)
MVP		0.43
MPC		0.75
ClinPred		0.11	T
GERP RS		4.6
BranchPoint Hunter		3.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.19
gMVP		0.38
Mutation Taster		=64/36	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs747903624; hg19: chr14-103934401;