10-13222161-C-T

Variant names:

• chr10-13222161-C-T
• rs760253387
• NM_145314.3:c.359G>A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_145314.3(UCMA):​c.359G>A​(p.Arg120His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000768 in 1,613,974 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000092 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000075 (0 hom.)
• Consequence: UCMA NM_145314.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.14

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.27495533).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UCMA	NM_145314.3	c.359G>A	p.Arg120His	missense_variant	Exon 5 of 5	ENST00000378681.8	NP_660357.2
UCMA	NM_001303118.2	c.263G>A	p.Arg88His	missense_variant	Exon 4 of 4		NP_001290047.1
UCMA	NM_001303119.2	c.197G>A	p.Arg66His	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.359G>A	p.Arg120His	missense_variant	Exon 5 of 5	1	NM_145314.3	ENSP00000367952.3
UCMA	ENST00000463405.2	c.293G>A	p.Arg98His	missense_variant	Exon 4 of 4	5		ENSP00000473368.1

Frequencies

GnomAD3 genomes AF: 0.0000920 AC: 14 AN: 152162 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000319 AC: 8 AN: 251112 Hom.: 0 AF XY: 0.0000368 AC XY: 5 AN XY: 135722

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: 0.0000704

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000752 AC: 110 AN: 1461812 Hom.: 0 Cov.: 30 AF XY: 0.0000756 AC XY: 55 AN XY: 727216

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000696

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000890

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000920 AC: 14 AN: 152162 Hom.: 0 Cov.: 31 AF XY: 0.0000807 AC XY: 6 AN XY: 74334

Gnomad4 AFR AF: 0.0000483

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000176

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000775 Hom.: 0

Bravo AF: 0.0000756

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.000164

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 23, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.359G>A (p.R120H) 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 359, causing the arginine (R) at amino acid position 120 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	0.17
BayesDel_addAF	Benign	-0.057	T
BayesDel_noAF	Benign	-0.13
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.26	T;.
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Uncertain	0.94	D;D
M_CAP	Benign	0.049	D
MetaRNN	Benign	0.27	T;T
MetaSVM	Uncertain	-0.24	T
MutationAssessor	Uncertain	2.7	M;.
PrimateAI	Benign	0.41	T
PROVEAN	Pathogenic	-4.6	D;.
REVEL	Uncertain	0.32
Sift	Pathogenic	0.0	D;.
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;.
Vest4		0.16
MVP		0.31
MPC		0.41
ClinPred		0.98	D
GERP RS		4.3
Varity_R		0.71
gMVP		0.51

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs760253387; hg19: chr10-13264161;