rs77245812

chr2-20003169-G-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP3 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_002381.5(MATN3):c.908C>T(p.Thr303Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0158 in 1,613,922 control chromosomes in the GnomAD database, including 321 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. T303T) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.012 (22 hom., cov: 33)
  • Exomes 𝑓: 0.016 (299 hom.)
• Consequence: MATN3 NM_002381.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts P:1 B:5 O:1
• Conservation: PhyloP100: 9.32

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 -19 ACMG points.

• PP3: Multiple lines of computational evidence support a deleterious effect 8: BayesDel_noAF, Cadd, Dann, Eigen, MutationAssessor, phyloP100way_vertebrate, PROVEAN, REVEL [when AlphaMissense, BayesDel_addAF, FATHMM_MKL, MetaRNN, MutationTaster, PrimateAI was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.018800974).
• BP6: Variant 2-20003169-G-A is Benign according to our data. Variant chr2-20003169-G-A is described in ClinVar as [Benign]. Clinvar id is 7542.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-20003169-G-A is described in Lovd as [Pathogenic]. Variant chr2-20003169-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0121 (1837/152310) while in subpopulation SAS AF= 0.0381 (184/4824). AF 95% confidence interval is 0.0336. There are 22 homozygotes in gnomad4. There are 872 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 22 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MATN3	NM_002381.5	c.908C>T	p.Thr303Met	missense_variant	3/8	ENST00000407540.8
WDR35-DT	NR_110235.1	n.364-851G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MATN3	ENST00000407540.8	c.908C>T	p.Thr303Met	missense_variant	3/8	1	NM_002381.5	P1
MATN3	ENST00000421259.2	c.791-1089C>T		intron_variant		1
WDR35-DT	ENST00000416575.2	n.357-851G>A		intron_variant, non_coding_transcript_variant		2
WDR35-DT	ENST00000658200.1	n.2226G>A		non_coding_transcript_exon_variant	3/3

Frequencies

GnomAD3 genomes AF: 0.0121 AC: 1840 AN: 152192 Hom.: 22 Cov.: 33

Gnomad AFR AF: 0.00297

Gnomad AMI AF: 0.111

Gnomad AMR AF: 0.00955

Gnomad ASJ AF: 0.0211

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0383

Gnomad FIN AF: 0.00339

Gnomad MID AF: 0.0411

Gnomad NFE AF: 0.0166

Gnomad OTH AF: 0.0158

GnomAD3 exomes AF: 0.0151 AC: 3771 AN: 249204 Hom.: 62 AF XY: 0.0171 AC XY: 2312 AN XY: 135194

Gnomad AFR exome AF: 0.00252

Gnomad AMR exome AF: 0.00519

Gnomad ASJ exome AF: 0.0199

Gnomad EAS exome AF: 0.000167

Gnomad SAS exome AF: 0.0444

Gnomad FIN exome AF: 0.00418

Gnomad NFE exome AF: 0.0160

Gnomad OTH exome AF: 0.0149

GnomAD4 exome AF: 0.0162 AC: 23730 AN: 1461612 Hom.: 299 Cov.: 31 AF XY: 0.0171 AC XY: 12423 AN XY: 727092

Gnomad4 AFR exome AF: 0.00254

Gnomad4 AMR exome AF: 0.00593

Gnomad4 ASJ exome AF: 0.0207

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.0443

Gnomad4 FIN exome AF: 0.00496

Gnomad4 NFE exome AF: 0.0159

Gnomad4 OTH exome AF: 0.0153

GnomAD4 genome AF: 0.0121 AC: 1837 AN: 152310 Hom.: 22 Cov.: 33 AF XY: 0.0117 AC XY: 872 AN XY: 74470

Gnomad4 AFR AF: 0.00296

Gnomad4 AMR AF: 0.00954

Gnomad4 ASJ AF: 0.0211

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0381

Gnomad4 FIN AF: 0.00339

Gnomad4 NFE AF: 0.0166

Gnomad4 OTH AF: 0.0156

Alfa AF: 0.0153 Hom.: 30

Bravo AF: 0.0109

TwinsUK AF: 0.0151 AC: 56

ALSPAC AF: 0.0150 AC: 58

ESP6500AA AF: 0.00494 AC: 20

ESP6500EA AF: 0.0146 AC: 122

ExAC AF: 0.0161 AC: 1950

Asia WGS AF: 0.0160 AC: 54 AN: 3478

EpiCase AF: 0.0173

EpiControl AF: 0.0178

ClinVar

Significance: Benign

Submissions summary: Pathogenic:1 Benign:5 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Multiple epiphyseal dysplasia type 5 Pathogenic:1 Benign:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 2004	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 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. -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

May 22, 2018

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

MATN3-related condition Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 28, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Connective tissue disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jan 31, 2022

- -

Osteoarthritis susceptibility 2 Other:1

risk factor, no assertion criteria provided

literature only

OMIM

Jun 01, 2003

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	-0.0054	T
BayesDel_noAF	Pathogenic	0.25
Cadd	Pathogenic	31
Dann	Pathogenic	1.0
DEOGEN2	Uncertain	0.78	D
Eigen	Pathogenic	0.91
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.92	D
MetaRNN	Benign	0.019	T
MetaSVM	Uncertain	0.68	D
MutationAssessor	Pathogenic	3.3	M
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.46	T
PROVEAN	Pathogenic	-5.3	D
REVEL	Pathogenic	0.66
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.32
MPC		0.76
ClinPred		0.046	T
GERP RS		5.5
Varity_R		0.78
gMVP		0.80

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs77245812; hg19: chr2-20202930; COSMIC: COSV99067488;