rs778372511

Variant names:

• chr10-13233571-T-G
• rs778372511
• NM_145314.3:c.187A>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_145314.3(UCMA):​c.187A>C​(p.Lys63Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000616 in 1,461,864 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: UCMA NM_145314.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.33
• Publications: 0 publications found

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

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=0.20507392).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_145314.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UCMA	NM_145314.3	MANE Select	c.187A>C	p.Lys63Gln	missense	Exon 3 of 5	NP_660357.2	Q8WVF2
	UCMA	NM_001303118.2		c.124+164A>C		intron	N/A	NP_001290047.1
	UCMA	NM_001303119.2		c.58+630A>C		intron	N/A	NP_001290048.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UCMA	ENST00000378681.8	TSL:1 MANE Select	c.187A>C	p.Lys63Gln	missense	Exon 3 of 5	ENSP00000367952.3	Q8WVF2
	UCMA	ENST00000463405.2	TSL:5	c.121A>C	p.Lys41Gln	missense	Exon 2 of 4	ENSP00000473368.1	R4GMV7
	UCMA	ENST00000914827.1		c.124+164A>C		intron	N/A	ENSP00000584886.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000795 AC: 2 AN: 251422 AF XY: 0.0000147

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: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000616 AC: 9 AN: 1461864 Hom.: 0 Cov.: 54 AF XY: 0.00000550 AC XY: 4 AN XY: 727234

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000540 AC: 6 AN: 1111996

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.094	T
Eigen	Benign	-0.018
Eigen_PC	Benign	0.049
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.71	T
M_CAP	Benign	0.0024	T
MetaRNN	Benign	0.21	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		2.3
PrimateAI	Benign	0.43	T
PROVEAN	Uncertain	-3.0	D
REVEL	Benign	0.090
Sift	Benign	0.045	D
Sift4G	Uncertain	0.054	T
Polyphen		0.56	P
Vest4		0.26
MutPred		0.12		Loss of methylation at K63 (P = 0.0159)
MVP		0.10
MPC		0.13
ClinPred		0.67	D
GERP RS		4.2
Varity_R		0.52
gMVP		0.26
Mutation Taster		=88/12	polymorphism

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

Other links and lift over

dbSNP: rs778372511; hg19: chr10-13275571;