Genetic Variant CNMD:p.Val147Leu (chr13-52724026-C-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

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

The NM_007015.3(CNMD):c.439G>T(p.Val147Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/23 in silico tools predict a benign outcome for this variant. 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. V147M) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 31)

Consequence

CNMD
NM_007015.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.639

Publications

1 publications found

Variant links:

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]

CNMD links:

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ACMG classification

Classification was made for transcript

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.439G>T	p.Val147Leu	missense	Exon 4 of 7	NP_008946.1	O75829-1
	CNMD	NM_001011705.2		c.439G>T	p.Val147Leu	missense	Exon 4 of 7	NP_001011705.1	O75829-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CNMD	ENST00000377962.8	TSL:1 MANE Select	c.439G>T	p.Val147Leu	missense	Exon 4 of 7	ENSP00000367198.3	O75829-1
CNMD	ENST00000448904.6	TSL:1	c.439G>T	p.Val147Leu	missense	Exon 4 of 7	ENSP00000388576.2	O75829-2
CNMD	ENST00000863287.1		c.439G>T	p.Val147Leu	missense	Exon 4 of 7	ENSP00000533346.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000398

AC:

AN:

251350

AF XY:

0.00

show subpopulations

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.088

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Benign

-0.46

CADD

Benign

0.0090

(source)

DANN

Benign

0.81

DEOGEN2

Benign

0.033

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.057

LIST_S2

Benign

0.59

M_CAP

Benign

0.013

MetaRNN

Benign

0.041

MetaSVM

Benign

-0.99

PhyloP100

-0.64

PrimateAI

Benign

0.28

PROVEAN

Benign

0.14

REVEL

Benign

0.064

Sift

Benign

0.41

Sift4G

Benign

0.40

Polyphen

0.0010

Vest4

0.032

MutPred

0.32

Gain of catalytic residue at Q150 (P = 9e-04)

MVP

0.092

MPC

0.17

ClinPred

0.028

GERP RS

-5.6

Varity_R

0.023

gMVP

0.45

Mutation Taster

=93/7

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.23

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.23

Position offset: -29

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over