Genetic Variant MARK3:p.Gly423Ala (chr14-103474996-G-C) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

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

The NM_001128918.3(MARK3):c.1268G>C(p.Gly423Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,456,844 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. G423E) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

MARK3
NM_001128918.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.97

Publications

0 publications found

Variant links:

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

MARK3 links:

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ACMG classification

Classification was made for transcript

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MARK3	NM_001128918.3	MANE Select	c.1268G>C	p.Gly423Ala	missense	Exon 13 of 18	NP_001122390.2	P27448-5
MARK3	NM_001128919.3		c.1268G>C	p.Gly423Ala	missense	Exon 13 of 17	NP_001122391.2	P27448-4
MARK3	NM_001437366.1		c.1214G>C	p.Gly405Ala	missense	Exon 12 of 17	NP_001424295.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MARK3	ENST00000429436.7	TSL:1 MANE Select	c.1268G>C	p.Gly423Ala	missense	Exon 13 of 18	ENSP00000411397.2	P27448-5
MARK3	ENST00000556744.2	TSL:1	c.1220G>C	p.Gly407Ala	missense	Exon 13 of 19	ENSP00000451623.2	H0YJI9
MARK3	ENST00000416682.6	TSL:1	c.1337G>C	p.Gly446Ala	missense	Exon 14 of 17	ENSP00000408092.2	P27448-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.86e-7

AC:

AN:

1456844

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

723746

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33378

American (AMR)

AF:

0.00

AC:

AN:

44628

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26086

East Asian (EAS)

AF:

0.00

AC:

AN:

39540

South Asian (SAS)

AF:

0.00

AC:

AN:

86136

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53366

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5748

European-Non Finnish (NFE)

AF:

9.03e-7

AC:

AN:

1107758

Other (OTH)

AF:

0.00

AC:

AN:

60204

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Uncertain

0.16

BayesDel_noAF

Uncertain

-0.010

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.60

Eigen

Uncertain

0.23

Eigen_PC

Uncertain

0.39

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.96

M_CAP

Benign

0.015

MetaRNN

Uncertain

0.46

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.9

PhyloP100

8.0

PrimateAI

Uncertain

0.73

PROVEAN

Uncertain

-3.6

REVEL

Benign

0.19

Sift

Benign

0.076

Sift4G

Benign

0.11

Polyphen

0.029

Vest4

0.68

MutPred

0.26

Gain of catalytic residue at D420 (P = 0.0851)

MVP

0.67

MPC

0.88

ClinPred

0.97

GERP RS

5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.53

gMVP

0.52

Mutation Taster

=13/87

disease causing

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over