13-52739109-C-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4 BP6_Moderate BP7 BS1 BS2

The NM_007015.3(CNMD):c.135G>T(p.Val45=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00123 in 1,571,620 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0072 (14 hom., cov: 32)
  • Exomes 𝑓: 0.00058 (2 hom.)
• Consequence: CNMD NM_007015.3 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.00400

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

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.09).
• BP6: Variant 13-52739109-C-A is Benign according to our data. Variant chr13-52739109-C-A is described in ClinVar as [Benign]. Clinvar id is 718599.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-0.004 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00721 (1097/152218) while in subpopulation AFR AF= 0.0255 (1060/41550). AF 95% confidence interval is 0.0242. There are 14 homozygotes in gnomad4. There are 500 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 14 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CNMD	NM_007015.3	c.135G>T	p.Val45=	synonymous_variant	2/7	ENST00000377962.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CNMD	ENST00000377962.8	c.135G>T	p.Val45=	synonymous_variant	2/7	1	NM_007015.3	P4
CNMD	ENST00000448904.6	c.135G>T	p.Val45=	synonymous_variant	2/7	1		A1
CNMD	ENST00000431550.1	c.-100G>T		5_prime_UTR_variant	1/4	2

Frequencies

GnomAD3 genomes AF: 0.00722 AC: 1098 AN: 152104 Hom.: 14 Cov.: 32

Gnomad AFR AF: 0.0256

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00144

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00479

GnomAD3 exomes AF: 0.00152 AC: 300 AN: 197018 Hom.: 2 AF XY: 0.00122 AC XY: 134 AN XY: 109902

Gnomad AFR exome AF: 0.0261

Gnomad AMR exome AF: 0.000770

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000749

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000225

Gnomad OTH exome AF: 0.000682

GnomAD4 exome AF: 0.000584 AC: 829 AN: 1419402 Hom.: 2 Cov.: 31 AF XY: 0.000520 AC XY: 367 AN XY: 706244

Gnomad4 AFR exome AF: 0.0238

Gnomad4 AMR exome AF: 0.00114

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000604

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000119

Gnomad4 OTH exome AF: 0.00130

GnomAD4 genome AF: 0.00721 AC: 1097 AN: 152218 Hom.: 14 Cov.: 32 AF XY: 0.00672 AC XY: 500 AN XY: 74404

Gnomad4 AFR AF: 0.0255

Gnomad4 AMR AF: 0.00144

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00474

Alfa AF: 0.00395 Hom.: 5

Bravo AF: 0.00822

Asia WGS AF: 0.000578 AC: 2 AN: 3474

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 22, 2018

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.090
Cadd	Benign	12
Dann	Benign	0.90

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs77837850; hg19: chr13-53313244;