13-52712755-C-A

Variant names:

• chr13-52712755-C-A
• rs985970015
• NM_007015.3:c.583G>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_007015.3(CNMD):​c.583G>T​(p.Asp195Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000716 in 1,397,162 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D195N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: CNMD NM_007015.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.08
• Publications: 0 publications found

Genes affected

CNMD (HGNC:17005): (chondromodulin) This gene encodes a glycosylated transmembrane protein that is cleaved to form a mature, secreted protein. The N-terminus of the precursor protein shares characteristics with other surfactant proteins and is sometimes called chondrosurfactant protein although no biological activity has yet been defined for it. The C-terminus of the precursor protein contains a 25 kDa mature protein called leukocyte cell-derived chemotaxin-1 or chondromodulin-1. The mature protein promotes chondrocyte growth and inhibits angiogenesis. This gene is expressed in the avascular zone of prehypertrophic cartilage and its expression decreases during chondrocyte hypertrophy and vascular invasion. The mature protein likely plays a role in endochondral bone development by permitting cartilaginous anlagen to be vascularized and replaced by bone. It may be involved also in the broad control of tissue vascularization during development. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_007015.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CNMD	NM_007015.3	MANE Select	c.583G>T	p.Asp195Tyr	missense	Exon 5 of 7	NP_008946.1	O75829-1
	CNMD	NM_001011705.2		c.583G>T	p.Asp195Tyr	missense	Exon 5 of 7	NP_001011705.1	O75829-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CNMD	ENST00000377962.8	TSL:1 MANE Select	c.583G>T	p.Asp195Tyr	missense	Exon 5 of 7	ENSP00000367198.3	O75829-1
	CNMD	ENST00000448904.6	TSL:1	c.583G>T	p.Asp195Tyr	missense	Exon 5 of 7	ENSP00000388576.2	O75829-2
	CNMD	ENST00000863287.1		c.583G>T	p.Asp195Tyr	missense	Exon 5 of 7	ENSP00000533346.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.16e-7 AC: 1 AN: 1397162 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 689266

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 31264

American (AMR) AF: 0.00 AC: 0 AN: 36400

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24658

East Asian (EAS) AF: 0.00 AC: 0 AN: 37354

South Asian (SAS) AF: 0.0000137 AC: 1 AN: 72744

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52170

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5552

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1079340

Other (OTH) AF: 0.00 AC: 0 AN: 57680

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.050
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.53	D
Eigen	Benign	-0.12
Eigen_PC	Benign	-0.27
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.055	D
MetaRNN	Uncertain	0.44	T
MetaSVM	Uncertain	-0.18	T
PhyloP100		1.1
PrimateAI	Benign	0.30	T
PROVEAN	Uncertain	-3.7	D
REVEL	Uncertain	0.58
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0030	D
Polyphen		0.89	P
Vest4		0.67
MutPred		0.65		Gain of catalytic residue at D195 (P = 0.0082)
MVP		0.68
MPC		0.61
ClinPred		0.96	D
GERP RS		-0.43
Varity_R		0.37
gMVP		0.73
Mutation Taster		=48/52	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs985970015; hg19: chr13-53286890;