10-27734625-C-A

Position:

• chr10-27734625-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_173576.3(MKX):​c.669G>T​(p.Leu223Phe) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MKX NM_173576.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.04

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MKX	NM_173576.3	c.669G>T	p.Leu223Phe	missense_variant	5/7	ENST00000419761.6	NP_775847.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MKX	ENST00000419761.6	c.669G>T	p.Leu223Phe	missense_variant	5/7	2	NM_173576.3	ENSP00000400896	P1
MKX	ENST00000375790.9	c.669G>T	p.Leu223Phe	missense_variant	5/7	1		ENSP00000364946	P1
MKX	ENST00000460919.2	c.669G>T	p.Leu223Phe	missense_variant	4/5	3		ENSP00000452751

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

MKX-related disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 09, 2023

The MKX c.669G>T variant is predicted to result in the amino acid substitution p.Leu223Phe. To our knowledge, this variant has not been reported in the literature or in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.040
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.31	T;T;.
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D;.;D
M_CAP	Benign	0.055	D
MetaRNN	Uncertain	0.65	D;D;D
MetaSVM	Uncertain	0.14	D
MutationAssessor	Uncertain	2.0	M;M;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-1.9	N;N;N
REVEL	Uncertain	0.42
Sift	Uncertain	0.0010	D;D;D
Sift4G	Uncertain	0.031	D;D;.
Polyphen		1.0	D;D;.
Vest4		0.80
MutPred		0.35		Gain of methylation at K219 (P = 0.0885);Gain of methylation at K219 (P = 0.0885);Gain of methylation at K219 (P = 0.0885);
MVP		0.52
MPC		0.59
ClinPred		0.98	D
GERP RS		5.6
Varity_R		0.39
gMVP		0.53

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

LitVar

Other links and lift over

dbSNP: rs1834709876; hg19: chr10-28023554;