rs41291317

Positions:

• chr10-13233764-A-G

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_145314.3(UCMA):​c.95T>C​(p.Met32Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0055 in 1,613,882 control chromosomes in the GnomAD database, including 36 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0056 (5 hom., cov: 31)
  • Exomes 𝑓: 0.0055 (31 hom.)
• Consequence: UCMA NM_145314.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.304

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 Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0050503314).
• BP6: Variant 10-13233764-A-G is Benign according to our data. Variant chr10-13233764-A-G is described in ClinVar as [Benign]. Clinvar id is 789201.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
UCMA	NM_145314.3	c.95T>C	p.Met32Thr	missense_variant	2/5	ENST00000378681.8	NP_660357.2
UCMA	NM_001303118.2	c.95T>C	p.Met32Thr	missense_variant	2/4		NP_001290047.1
UCMA	NM_001303119.2	c.58+437T>C		intron_variant			NP_001290048.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
UCMA	ENST00000378681.8	c.95T>C	p.Met32Thr	missense_variant	2/5	1	NM_145314.3	ENSP00000367952.3
UCMA	ENST00000463405.2	c.59-131T>C		intron_variant		5		ENSP00000473368.1

Frequencies

GnomAD3 genomes AF: 0.00563 AC: 855 AN: 151896 Hom.: 5 Cov.: 31

Gnomad AFR AF: 0.000847

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00610

Gnomad ASJ AF: 0.00634

Gnomad EAS AF: 0.000389

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00935

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00863

Gnomad OTH AF: 0.00720

GnomAD3 exomes AF: 0.00485 AC: 1219 AN: 251420 Hom.: 5 AF XY: 0.00458 AC XY: 623 AN XY: 135888

Gnomad AFR exome AF: 0.000738

Gnomad AMR exome AF: 0.00359

Gnomad ASJ exome AF: 0.00526

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000163

Gnomad FIN exome AF: 0.00929

Gnomad NFE exome AF: 0.00696

Gnomad OTH exome AF: 0.00538

GnomAD4 exome AF: 0.00549 AC: 8023 AN: 1461866 Hom.: 31 Cov.: 34 AF XY: 0.00536 AC XY: 3897 AN XY: 727238

Gnomad4 AFR exome AF: 0.000657

Gnomad4 AMR exome AF: 0.00365

Gnomad4 ASJ exome AF: 0.00520

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000278

Gnomad4 FIN exome AF: 0.00964

Gnomad4 NFE exome AF: 0.00615

Gnomad4 OTH exome AF: 0.00525

GnomAD4 genome AF: 0.00562 AC: 855 AN: 152016 Hom.: 5 Cov.: 31 AF XY: 0.00610 AC XY: 453 AN XY: 74290

Gnomad4 AFR AF: 0.000844

Gnomad4 AMR AF: 0.00610

Gnomad4 ASJ AF: 0.00634

Gnomad4 EAS AF: 0.000389

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00935

Gnomad4 NFE AF: 0.00863

Gnomad4 OTH AF: 0.00712

Alfa AF: 0.00690 Hom.: 6

Bravo AF: 0.00424

TwinsUK AF: 0.00620 AC: 23

ALSPAC AF: 0.00467 AC: 18

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00791 AC: 68

ExAC AF: 0.00472 AC: 573

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00616

EpiControl AF: 0.00486

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	May 04, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.043
BayesDel_addAF	Benign	-0.71	T
BayesDel_noAF	Benign	-0.78
CADD	Benign	0.042
DANN	Benign	0.20
DEOGEN2	Benign	0.0019	T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.0051	N
LIST_S2	Benign	0.24	T
MetaRNN	Benign	0.0051	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.69	N
PrimateAI	Benign	0.23	T
PROVEAN	Benign	0.35	N
REVEL	Benign	0.019
Sift	Benign	0.63	T
Sift4G	Benign	0.64	T
Polyphen		0.0	B
Vest4		0.10
MVP		0.030
MPC		0.067
ClinPred		0.0015	T
GERP RS		-4.1
Varity_R		0.082
gMVP		0.074

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: rs41291317; hg19: chr10-13275764;