Genetic Variant MARK3:p.Gln50His (chr14-103405174-A-C) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001128918.3(MARK3):c.150A>C(p.Gln50His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000345 in 1,447,508 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. Q50Q) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000035 ( 0 hom. )

Consequence

MARK3
NM_001128918.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.250

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 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.15364522).

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.150A>C	p.Gln50His	missense	Exon 2 of 18	NP_001122390.2	P27448-5
MARK3	NM_001128919.3		c.150A>C	p.Gln50His	missense	Exon 2 of 17	NP_001122391.2	P27448-4
MARK3	NM_001437366.1		c.150A>C	p.Gln50His	missense	Exon 2 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.150A>C	p.Gln50His	missense	Exon 2 of 18	ENSP00000411397.2	P27448-5
MARK3	ENST00000556744.2	TSL:1	c.150A>C	p.Gln50His	missense	Exon 2 of 19	ENSP00000451623.2	H0YJI9
MARK3	ENST00000416682.6	TSL:1	c.150A>C	p.Gln50His	missense	Exon 2 of 17	ENSP00000408092.2	P27448-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000345

AC:

AN:

1447508

Hom.:

Cov.:

AF XY:

0.00000555

AC XY:

AN XY:

720102

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32394

American (AMR)

AF:

0.00

AC:

AN:

39854

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25324

East Asian (EAS)

AF:

0.00

AC:

AN:

39560

South Asian (SAS)

AF:

0.00

AC:

AN:

83310

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53272

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5716

European-Non Finnish (NFE)

AF:

0.00000451

AC:

AN:

1108256

Other (OTH)

AF:

0.00

AC:

AN:

59822

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.455

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

0.18

BayesDel_addAF

Benign

-0.031

BayesDel_noAF

Benign

-0.28

CADD

Benign

(source)

DANN

Benign

0.95

DEOGEN2

Uncertain

0.56

Eigen

Benign

-0.73

Eigen_PC

Benign

-0.73

FATHMM_MKL

Benign

0.64

LIST_S2

Uncertain

0.94

M_CAP

Benign

0.034

MetaRNN

Benign

0.15

MetaSVM

Benign

-0.90

MutationAssessor

Benign

1.4

PhyloP100

-0.25

PrimateAI

Uncertain

0.73

PROVEAN

Benign

-2.0

REVEL

Benign

0.19

Sift

Uncertain

0.0040

Sift4G

Benign

0.10

Polyphen

0.035

Vest4

0.39

MutPred

0.34

Gain of catalytic residue at A47 (P = 0.0072)

MVP

0.61

MPC

0.29

ClinPred

0.41

GERP RS

-3.5

Varity_R

0.56

gMVP

0.56

Mutation Taster

=80/20

polymorphism

(source)

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

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