13-52724005-A-T

Variant names:

• chr13-52724005-A-T
• NM_007015.3:c.460T>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_007015.3(CNMD):​c.460T>A​(p.Ser154Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000000687 in 1,456,238 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: CNMD NM_007015.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.12
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.21417308).

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.460T>A	p.Ser154Thr	missense	Exon 4 of 7	NP_008946.1	O75829-1
	CNMD	NM_001011705.2		c.460T>A	p.Ser154Thr	missense	Exon 4 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.460T>A	p.Ser154Thr	missense	Exon 4 of 7	ENSP00000367198.3	O75829-1
	CNMD	ENST00000448904.6	TSL:1	c.460T>A	p.Ser154Thr	missense	Exon 4 of 7	ENSP00000388576.2	O75829-2
	CNMD	ENST00000863287.1		c.460T>A	p.Ser154Thr	missense	Exon 4 of 7	ENSP00000533346.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.87e-7 AC: 1 AN: 1456238 Hom.: 0 Cov.: 29 AF XY: 0.00000138 AC XY: 1 AN XY: 724852

African (AFR) AF: 0.00 AC: 0 AN: 33362

American (AMR) AF: 0.00 AC: 0 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26098

East Asian (EAS) AF: 0.00 AC: 0 AN: 39672

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86136

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1106876

Other (OTH) AF: 0.00 AC: 0 AN: 60210

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.057	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	18
DANN	Benign	0.91
DEOGEN2	Benign	0.14	T
Eigen	Benign	-0.13
Eigen_PC	Benign	0.068
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.66	T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.21	T
MetaSVM	Benign	-0.57	T
PhyloP100		5.1
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-0.85	N
REVEL	Benign	0.27
Sift	Benign	0.72	T
Sift4G	Benign	0.28	T
Polyphen		0.073	B
Vest4		0.22
MutPred		0.44		Gain of catalytic residue at Q150 (P = 2e-04)
MVP		0.54
MPC		0.25
ClinPred		0.48	T
GERP RS		5.5
Varity_R		0.099
gMVP		0.55
Mutation Taster		=85/15	polymorphism

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

Other links and lift over

hg19: chr13-53298140;