2-20003168-C-T

Variant names:

• chr2-20003168-C-T
• rs28452699
• NM_002381.5:c.909G>A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_002381.5(MATN3):​c.909G>A​(p.Thr303Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.213 in 1,613,434 control chromosomes in the GnomAD database, including 38,078 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.20 (3189 hom., cov: 32)
  • Exomes 𝑓: 0.22 (34889 hom.)
• Consequence: MATN3 NM_002381.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -3.74

Genes affected

MATN3 (HGNC:6909): (matrilin 3) This gene encodes a member of von Willebrand factor A domain containing protein family. This family of proteins is thought to be involved in the formation of filamentous networks in the extracellular matrices of various tissues. This protein contains two von Willebrand factor A domains; it is present in the cartilage extracellular matrix and has a role in the development and homeostasis of cartilage and bone. Mutations in this gene result in multiple epiphyseal dysplasia. [provided by RefSeq, Jul 2008]

WDR35-DT (HGNC:55818): (WDR35 divergent transcript)

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.62).
• BP6: Variant 2-20003168-C-T is Benign according to our data. Variant chr2-20003168-C-T is described in ClinVar as [Benign]. Clinvar id is 258649.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.74 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.221 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MATN3	NM_002381.5	c.909G>A	p.Thr303Thr	synonymous_variant	Exon 3 of 8	ENST00000407540.8	NP_002372.1
WDR35-DT	NR_110235.1	n.364-852C>T		intron_variant	Intron 2 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MATN3	ENST00000407540.8	c.909G>A	p.Thr303Thr	synonymous_variant	Exon 3 of 8	1	NM_002381.5	ENSP00000383894.3
MATN3	ENST00000421259.2	c.791-1088G>A		intron_variant	Intron 2 of 6	1		ENSP00000398753.2
WDR35-DT	ENST00000658200.1	n.2225C>T		non_coding_transcript_exon_variant	Exon 3 of 3
WDR35-DT	ENST00000416575.2	n.357-852C>T		intron_variant	Intron 2 of 2	2

Frequencies

GnomAD3 genomes AF: 0.198 AC: 30046 AN: 151980 Hom.: 3184 Cov.: 32

Gnomad AFR AF: 0.159

Gnomad AMI AF: 0.140

Gnomad AMR AF: 0.215

Gnomad ASJ AF: 0.185

Gnomad EAS AF: 0.0326

Gnomad SAS AF: 0.180

Gnomad FIN AF: 0.254

Gnomad MID AF: 0.0828

Gnomad NFE AF: 0.224

Gnomad OTH AF: 0.197

GnomAD3 exomes AF: 0.204 AC: 50833 AN: 249116 Hom.: 5686 AF XY: 0.203 AC XY: 27491 AN XY: 135160

Gnomad AFR exome AF: 0.155

Gnomad AMR exome AF: 0.240

Gnomad ASJ exome AF: 0.192

Gnomad EAS exome AF: 0.0284

Gnomad SAS exome AF: 0.182

Gnomad FIN exome AF: 0.253

Gnomad NFE exome AF: 0.225

Gnomad OTH exome AF: 0.211

GnomAD4 exome AF: 0.215 AC: 314342 AN: 1461334 Hom.: 34889 Cov.: 32 AF XY: 0.214 AC XY: 155473 AN XY: 726964

Gnomad4 AFR exome AF: 0.156

Gnomad4 AMR exome AF: 0.234

Gnomad4 ASJ exome AF: 0.192

Gnomad4 EAS exome AF: 0.0504

Gnomad4 SAS exome AF: 0.183

Gnomad4 FIN exome AF: 0.251

Gnomad4 NFE exome AF: 0.224

Gnomad4 OTH exome AF: 0.203

GnomAD4 genome AF: 0.198 AC: 30083 AN: 152100 Hom.: 3189 Cov.: 32 AF XY: 0.198 AC XY: 14744 AN XY: 74370

Gnomad4 AFR AF: 0.159

Gnomad4 AMR AF: 0.216

Gnomad4 ASJ AF: 0.185

Gnomad4 EAS AF: 0.0327

Gnomad4 SAS AF: 0.180

Gnomad4 FIN AF: 0.254

Gnomad4 NFE AF: 0.224

Gnomad4 OTH AF: 0.195

Alfa AF: 0.209 Hom.: 4244

Bravo AF: 0.193

Asia WGS AF: 0.122 AC: 424 AN: 3478

EpiCase AF: 0.214

EpiControl AF: 0.213

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

May 04, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Multiple epiphyseal dysplasia type 5 Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.62
CADD	Benign	1.6
DANN	Benign	0.81

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: rs28452699; hg19: chr2-20202929; COSMIC: COSV68099679;