rs80070283

Positions:

• chr10-13229628-A-G

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_145314.3(UCMA):​c.302T>C​(p.Val101Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00064 in 1,613,968 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0034 (5 hom., cov: 31)
  • Exomes 𝑓: 0.00035 (5 hom.)
• Consequence: UCMA NM_145314.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.36

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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.006891668).
• 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.302T>C	p.Val101Ala	missense_variant	4/5	ENST00000378681.8	NP_660357.2
UCMA	NM_001303118.2	c.206T>C	p.Val69Ala	missense_variant	3/4		NP_001290047.1
UCMA	NM_001303119.2	c.140T>C	p.Val47Ala	missense_variant	2/3		NP_001290048.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
UCMA	ENST00000378681.8	c.302T>C	p.Val101Ala	missense_variant	4/5	1	NM_145314.3	ENSP00000367952.3
UCMA	ENST00000463405.2	c.236T>C	p.Val79Ala	missense_variant	3/4	5		ENSP00000473368.1

Frequencies

GnomAD3 genomes AF: 0.00343 AC: 521 AN: 152034 Hom.: 5 Cov.: 31

Gnomad AFR AF: 0.0117

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00170

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00336

GnomAD3 exomes AF: 0.000867 AC: 218 AN: 251400 Hom.: 1 AF XY: 0.000684 AC XY: 93 AN XY: 135880

Gnomad AFR exome AF: 0.0118

Gnomad AMR exome AF: 0.000434

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000528

Gnomad OTH exome AF: 0.000652

GnomAD4 exome AF: 0.000351 AC: 513 AN: 1461818 Hom.: 5 Cov.: 31 AF XY: 0.000307 AC XY: 223 AN XY: 727214

Gnomad4 AFR exome AF: 0.0123

Gnomad4 AMR exome AF: 0.000537

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: 0.00000719

Gnomad4 OTH exome AF: 0.000960

GnomAD4 genome AF: 0.00342 AC: 520 AN: 152150 Hom.: 5 Cov.: 31 AF XY: 0.00332 AC XY: 247 AN XY: 74388

Gnomad4 AFR AF: 0.0117

Gnomad4 AMR AF: 0.00170

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00332

Alfa AF: 0.000558 Hom.: 0

Bravo AF: 0.00431

ESP6500AA AF: 0.00885 AC: 39

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00101 AC: 123

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	14
DANN	Benign	0.97
DEOGEN2	Benign	0.031	T;.
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.25
FATHMM_MKL	Benign	0.68	D
LIST_S2	Benign	0.70	T;T
MetaRNN	Benign	0.0069	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.6	L;.
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-2.0	N;.
REVEL	Benign	0.048
Sift	Benign	0.27	T;.
Sift4G	Benign	0.32	T;T
Polyphen		0.34	B;.
Vest4		0.27
MVP		0.16
MPC		0.085
ClinPred		0.016	T
GERP RS		2.9
Varity_R		0.13
gMVP		0.32

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: rs80070283; hg19: chr10-13271628; COSMIC: COSV99059960;