Genetic Variant MKX:p.Gly44Ser (chr10-27743286-C-T) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_173576.3(MKX):c.130G>A(p.Gly44Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000214 in 1,399,688 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 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. G44R) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

MKX
NM_173576.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.03

Publications

0 publications found

Variant links:

Genes affected

MKX (HGNC:23729): (mohawk homeobox) The protein encoded by this gene is an IRX family-related homeobox protein that may play a role in cell adhesion. Studies in mice suggest that this protein may be a regulator of tendon development. Two transcript variants encoding the same protein have been found for this gene.[provided by RefSeq, Jun 2011]

MKX links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MKX	NM_173576.3 link	c.130G>A	p.Gly44Ser	missense_variant	Exon 2 of 7	ENST00000419761.6	NP_775847.2	Q8IYA7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
MKX	ENST00000419761.6 link	c.130G>A	p.Gly44Ser	missense_variant	Exon 2 of 7	2	NM_173576.3	ENSP00000400896.1	Q8IYA7
MKX	ENST00000375790.9 link	c.130G>A	p.Gly44Ser	missense_variant	Exon 2 of 7	1		ENSP00000364946.4	Q8IYA7
MKX	ENST00000460919.2 link	c.130G>A	p.Gly44Ser	missense_variant	Exon 1 of 5	3		ENSP00000452751.1	H0YKC7
MKX	ENST00000561227.1 link	c.130G>A	p.Gly44Ser	missense_variant	Exon 2 of 2	5		ENSP00000453746.1	H0YMU2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000529

AC:

AN:

189054

AF XY:

0.00000955

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

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:

0.00000214

AC:

AN:

1399688

Hom.:

Cov.:

AF XY:

0.00000288

AC XY:

AN XY:

694284

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

28780

American (AMR)

AF:

0.00

AC:

AN:

32724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24038

East Asian (EAS)

AF:

0.00

AC:

AN:

34406

South Asian (SAS)

AF:

0.0000130

AC:

AN:

76698

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52334

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5582

European-Non Finnish (NFE)

AF:

0.00000184

AC:

AN:

1087332

Other (OTH)

AF:

0.00

AC:

AN:

57794

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.458

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 v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.078

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Benign

-0.40

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.063

T;T;.;.

Eigen

Benign

-0.28

Eigen_PC

Benign

-0.070

FATHMM_MKL

Uncertain

0.85

LIST_S2

Benign

0.78

T;.;T;T

M_CAP

Uncertain

0.16

MetaRNN

Benign

0.17

T;T;T;T

MetaSVM

Benign

-0.98

MutationAssessor

Benign

0.69

N;N;.;.

PhyloP100

2.0

PrimateAI

Uncertain

0.63

PROVEAN

Benign

-0.89

N;N;N;D

REVEL

Benign

0.067

Sift

Benign

0.085

T;T;T;T

Sift4G

Benign

0.62

T;T;.;T

Polyphen

0.079

B;B;.;.

Vest4

0.28

MutPred

0.16

Gain of phosphorylation at G44 (P = 0.0168);Gain of phosphorylation at G44 (P = 0.0168);Gain of phosphorylation at G44 (P = 0.0168);Gain of phosphorylation at G44 (P = 0.0168);

MVP

0.43

MPC

0.15

ClinPred

0.37

GERP RS

4.4

PromoterAI

0.12

Neutral

(source)

Varity_R

0.14

gMVP

0.32

Mutation Taster

=88/12

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.80

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.80

Position offset: 4

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over