10-13222116-C-T

Variant names:

• chr10-13222116-C-T
• rs753490238
• NM_145314.3:c.404G>A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_145314.3(UCMA):​c.404G>A​(p.Arg135His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000363 in 1,461,832 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.000036 (2 hom.)
• Consequence: UCMA NM_145314.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.28

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 Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.157893).
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UCMA	NM_145314.3	c.404G>A	p.Arg135His	missense_variant	Exon 5 of 5	ENST00000378681.8	NP_660357.2
UCMA	NM_001303118.2	c.308G>A	p.Arg103His	missense_variant	Exon 4 of 4		NP_001290047.1
UCMA	NM_001303119.2	c.242G>A	p.Arg81His	missense_variant	Exon 3 of 3		NP_001290048.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
UCMA	ENST00000378681.8	c.404G>A	p.Arg135His	missense_variant	Exon 5 of 5	1	NM_145314.3	ENSP00000367952.3
UCMA	ENST00000463405.2	c.338G>A	p.Arg113His	missense_variant	Exon 4 of 4	5		ENSP00000473368.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.0000717 AC: 18 AN: 251182 Hom.: 1 AF XY: 0.000103 AC XY: 14 AN XY: 135742

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: 0.000523

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000363 AC: 53 AN: 1461832 Hom.: 2 Cov.: 30 AF XY: 0.0000509 AC XY: 37 AN XY: 727216

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.000487

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000630

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 31

Alfa AF: 0.0000660 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.0000824 AC: 10

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 17, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.404G>A (p.R135H) alteration is located in exon 5 (coding exon 5) of the UCMA gene. This alteration results from a G to A substitution at nucleotide position 404, causing the arginine (R) at amino acid position 135 to be replaced by a histidine (H). 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	0.085
BayesDel_addAF	Benign	-0.029	T
BayesDel_noAF	Uncertain	0.060
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.073	T;.
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Uncertain	0.87	D;D
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.16	T;T
MetaSVM	Uncertain	-0.27	T
MutationAssessor	Uncertain	2.3	M;.
PrimateAI	Benign	0.39	T
PROVEAN	Uncertain	-3.6	D;.
REVEL	Uncertain	0.43
Sift	Pathogenic	0.0	D;.
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;.
Vest4		0.17
MutPred		0.36		Loss of stability (P = 0.0277);.;
MVP		0.21
MPC		0.12
ClinPred		0.54	D
GERP RS		5.2
Varity_R		0.64
gMVP		0.44

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: rs753490238; hg19: chr10-13264116; COSMIC: COSV66321951; COSMIC: COSV66321951;