10-13233576-C-T

Variant names:

• chr10-13233576-C-T
• rs377345564
• NM_145314.3:c.182G>A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_145314.3(UCMA):​c.182G>A​(p.Arg61His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000052 in 1,613,922 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000047 (0 hom.)
• Consequence: UCMA NM_145314.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.755

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 -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.05607441).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UCMA	NM_145314.3	c.182G>A	p.Arg61His	missense_variant	Exon 3 of 5	ENST00000378681.8	NP_660357.2
UCMA	NM_001303118.2	c.124+159G>A		intron_variant	Intron 2 of 3		NP_001290047.1
UCMA	NM_001303119.2	c.58+625G>A		intron_variant	Intron 1 of 2		NP_001290048.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
UCMA	ENST00000378681.8	c.182G>A	p.Arg61His	missense_variant	Exon 3 of 5	1	NM_145314.3	ENSP00000367952.3
UCMA	ENST00000463405.2	c.116G>A	p.Arg39His	missense_variant	Exon 2 of 4	5		ENSP00000473368.1

Frequencies

GnomAD3 genomes AF: 0.000105 AC: 16 AN: 152052 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000525

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.0000398 AC: 10 AN: 251434 Hom.: 0 AF XY: 0.0000442 AC XY: 6 AN XY: 135900

Gnomad AFR exome AF: 0.0000615

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: 0.0000615

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.0000465 AC: 68 AN: 1461870 Hom.: 0 Cov.: 54 AF XY: 0.0000426 AC XY: 31 AN XY: 727238

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.0000374

Gnomad4 NFE exome AF: 0.0000477

Gnomad4 OTH exome AF: 0.0000828

GnomAD4 genome AF: 0.000105 AC: 16 AN: 152052 Hom.: 0 Cov.: 32 AF XY: 0.0000943 AC XY: 7 AN XY: 74262

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000525

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000943

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.0000480 Hom.: 0

Bravo AF: 0.000193

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000659 AC: 8

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 19, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.182G>A (p.R61H) alteration is located in exon 3 (coding exon 3) of the UCMA gene. This alteration results from a G to A substitution at nucleotide position 182, causing the arginine (R) at amino acid position 61 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	0.14
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	17
DANN	Uncertain	1.0
DEOGEN2	Benign	0.25	T;.
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.43
FATHMM_MKL	Benign	0.22	N
LIST_S2	Uncertain	0.89	D;D
M_CAP	Benign	0.0041	T
MetaRNN	Benign	0.056	T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Uncertain	2.6	M;.
PrimateAI	Benign	0.29	T
PROVEAN	Pathogenic	-4.6	D;.
REVEL	Benign	0.077
Sift	Uncertain	0.028	D;.
Sift4G	Uncertain	0.025	D;D
Polyphen		0.26	B;.
Vest4		0.26
MVP		0.076
MPC		0.12
ClinPred		0.26	T
GERP RS		2.4
Varity_R		0.16
gMVP		0.37

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: rs377345564; hg19: chr10-13275576; COSMIC: COSV66321697;