10-27734602-A-G

Position:

• chr10-27734602-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_173576.3(MKX):​c.692T>C​(p.Leu231Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 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: 7.24

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.774

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MKX	NM_173576.3	c.692T>C	p.Leu231Ser	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.692T>C	p.Leu231Ser	missense_variant	5/7	2	NM_173576.3	ENSP00000400896	P1
MKX	ENST00000375790.9	c.692T>C	p.Leu231Ser	missense_variant	5/7	1		ENSP00000364946	P1
MKX	ENST00000460919.2	c.692T>C	p.Leu231Ser	missense_variant	4/5	3		ENSP00000452751

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 17, 2024

The c.692T>C (p.L231S) alteration is located in exon 5 (coding exon 4) of the MKX gene. This alteration results from a T to C substitution at nucleotide position 692, causing the leucine (L) at amino acid position 231 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.16
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.18	T;T;.
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	D;.;D
M_CAP	Benign	0.063	D
MetaRNN	Pathogenic	0.77	D;D;D
MetaSVM	Uncertain	-0.18	T
MutationAssessor	Uncertain	2.0	M;M;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.79	T
PROVEAN	Benign	-1.6	N;N;N
REVEL	Uncertain	0.46
Sift	Pathogenic	0.0	D;D;D
Sift4G	Uncertain	0.0060	D;D;.
Polyphen		0.99	D;D;.
Vest4		0.88
MutPred		0.46		Loss of stability (P = 0.0086);Loss of stability (P = 0.0086);Loss of stability (P = 0.0086);
MVP		0.73
MPC		0.67
ClinPred		0.96	D
GERP RS		5.8
Varity_R		0.39
gMVP		0.47

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr10-28023531;