2-20005919-C-T

Position:

• chr2-20005919-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The ENST00000407540.8(MATN3):​c.615G>A​(p.Glu205=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.445 in 1,612,252 control chromosomes in the GnomAD database, including 163,336 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.47 (17086 hom., cov: 32)
  • Exomes 𝑓: 0.44 (146250 hom.)
• Consequence: MATN3 ENST00000407540.8 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.310

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]

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.39).
• BP6: Variant 2-20005919-C-T is Benign according to our data. Variant chr2-20005919-C-T is described in ClinVar as [Benign]. Clinvar id is 195170.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.31 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.619 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MATN3	NM_002381.5	c.615G>A	p.Glu205=	synonymous_variant	2/8	ENST00000407540.8	NP_002372.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MATN3	ENST00000407540.8	c.615G>A	p.Glu205=	synonymous_variant	2/8	1	NM_002381.5	ENSP00000383894	P1
MATN3	ENST00000421259.2	c.615G>A	p.Glu205=	synonymous_variant	2/7	1		ENSP00000398753

Frequencies

GnomAD3 genomes AF: 0.470 AC: 71353 AN: 151926 Hom.: 17062 Cov.: 32

Gnomad AFR AF: 0.519

Gnomad AMI AF: 0.532

Gnomad AMR AF: 0.495

Gnomad ASJ AF: 0.409

Gnomad EAS AF: 0.637

Gnomad SAS AF: 0.588

Gnomad FIN AF: 0.430

Gnomad MID AF: 0.417

Gnomad NFE AF: 0.421

Gnomad OTH AF: 0.476

GnomAD3 exomes AF: 0.473 AC: 116386 AN: 245802 Hom.: 28198 AF XY: 0.475 AC XY: 63416 AN XY: 133418

Gnomad AFR exome AF: 0.515

Gnomad AMR exome AF: 0.493

Gnomad ASJ exome AF: 0.414

Gnomad EAS exome AF: 0.631

Gnomad SAS exome AF: 0.591

Gnomad FIN exome AF: 0.435

Gnomad NFE exome AF: 0.418

Gnomad OTH exome AF: 0.467

GnomAD4 exome AF: 0.443 AC: 646821 AN: 1460206 Hom.: 146250 Cov.: 63 AF XY: 0.447 AC XY: 324334 AN XY: 726294

Gnomad4 AFR exome AF: 0.528

Gnomad4 AMR exome AF: 0.487

Gnomad4 ASJ exome AF: 0.422

Gnomad4 EAS exome AF: 0.695

Gnomad4 SAS exome AF: 0.588

Gnomad4 FIN exome AF: 0.430

Gnomad4 NFE exome AF: 0.419

Gnomad4 OTH exome AF: 0.450

GnomAD4 genome AF: 0.470 AC: 71427 AN: 152046 Hom.: 17086 Cov.: 32 AF XY: 0.474 AC XY: 35269 AN XY: 74336

Gnomad4 AFR AF: 0.519

Gnomad4 AMR AF: 0.496

Gnomad4 ASJ AF: 0.409

Gnomad4 EAS AF: 0.637

Gnomad4 SAS AF: 0.587

Gnomad4 FIN AF: 0.430

Gnomad4 NFE AF: 0.421

Gnomad4 OTH AF: 0.481

Alfa AF: 0.429 Hom.: 17261

Bravo AF: 0.471

Asia WGS AF: 0.621 AC: 2158 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 08, 2015	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Multiple epiphyseal dysplasia type 5 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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	-0.39
CADD	Benign	8.0
DANN	Benign	0.71

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: rs28401180; hg19: chr2-20205680; COSMIC: COSV68100410; COSMIC: COSV68100410;