10-13229626-C-G

Position:

• chr10-13229626-C-G

Variant summary

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

The NM_145314.3(UCMA):​c.304G>C​(p.Glu102Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: UCMA NM_145314.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.28

Genes affected

UCMA (HGNC:25205): (upper zone of growth plate and cartilage matrix associated) This gene encodes a chondrocyte-specific, highly charged protein that is abundantly expressed in the upper immature zone of fetal and juvenile epiphyseal cartilage. The encoded protein undergoes proteolytic processing to generate a mature protein that is secreted into the extracellular matrix. The glutamic acid residues in the encoded protein undergo gamma carboxylation in a vitamin K-dependent manner. Undercarboxylation of the encoded protein is associated with osteoarthritis in humans. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jul 2015]

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
UCMA	NM_145314.3	c.304G>C	p.Glu102Gln	missense_variant	4/5	ENST00000378681.8	NP_660357.2
UCMA	NM_001303118.2	c.208G>C	p.Glu70Gln	missense_variant	3/4		NP_001290047.1
UCMA	NM_001303119.2	c.142G>C	p.Glu48Gln	missense_variant	2/3		NP_001290048.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
UCMA	ENST00000378681.8	c.304G>C	p.Glu102Gln	missense_variant	4/5	1	NM_145314.3	ENSP00000367952.3
UCMA	ENST00000463405.2	c.238G>C	p.Glu80Gln	missense_variant	3/4	5		ENSP00000473368.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251340 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135848

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 SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ExAC AF: 0.00000824 AC: 1

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

Feb 28, 2024

The c.304G>C (p.E102Q) alteration is located in exon 4 (coding exon 4) of the UCMA gene. This alteration results from a G to C substitution at nucleotide position 304, causing the glutamic acid (E) at amino acid position 102 to be replaced by a glutamine (Q). 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	Benign	0.30
BayesDel_addAF	Uncertain	0.038	T
BayesDel_noAF	Benign	-0.18
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.20	T;.
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.79	T;T
M_CAP	Benign	0.0078	T
MetaRNN	Uncertain	0.46	T;T
MetaSVM	Uncertain	-0.21	T
MutationAssessor	Uncertain	2.6	M;.
PrimateAI	Benign	0.48	T
PROVEAN	Uncertain	-2.5	N;.
REVEL	Benign	0.16
Sift	Uncertain	0.023	D;.
Sift4G	Uncertain	0.028	D;D
Polyphen		1.0	D;.
Vest4		0.48
MutPred		0.044		Loss of helix (P = 0.2022);.;
MVP		0.28
MPC		0.34
ClinPred		0.95	D
GERP RS		5.2
Varity_R		0.35
gMVP		0.33

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: rs776653974; hg19: chr10-13271626;