rs77245812

Variant names:

• chr2-20003169-G-A
• rs77245812
• NM_002381.5:c.908C>T

Variant summary

Our verdict is Benign. The variant received -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:7 O:1
• Conservation: PhyloP100: 9.32
• Publications: 24 publications found

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

Our verdict: Benign. The variant received -19 ACMG points.

• PP3: Multiple lines of computational evidence support a deleterious effect 9: BayesDel_noAF, Cadd, Dann, Eigen, MutationAssessor, phyloP100way_vertebrate, PROVEAN, REVEL, REVEL [when AlphaMissense, BayesDel_addAF, max_spliceai, 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 VariationId is 7542.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 22 AR,AD,Unknown gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002381.5. 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
	MATN3	NM_002381.5	MANE Select	c.908C>T	p.Thr303Met	missense	Exon 3 of 8	NP_002372.1
	WDR35-DT	NR_110235.1		n.364-851G>A		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MATN3	ENST00000407540.8	TSL:1 MANE Select	c.908C>T	p.Thr303Met	missense	Exon 3 of 8	ENSP00000383894.3
	MATN3	ENST00000421259.2	TSL:1	c.791-1089C>T		intron	N/A	ENSP00000398753.2
	MATN3	ENST00000856777.1		c.908C>T	p.Thr303Met	missense	Exon 3 of 8	ENSP00000526836.1

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

GnomAD2 exomes AF: 0.0151 AC: 3771 AN: 249204 AF XY: 0.0171

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 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

African (AFR) AF: 0.00254 AC: 85 AN: 33476

American (AMR) AF: 0.00593 AC: 265 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0207 AC: 540 AN: 26134

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39696

South Asian (SAS) AF: 0.0443 AC: 3825 AN: 86248

European-Finnish (FIN) AF: 0.00496 AC: 265 AN: 53386

Middle Eastern (MID) AF: 0.0232 AC: 134 AN: 5766

European-Non Finnish (NFE) AF: 0.0159 AC: 17689 AN: 1111816

Other (OTH) AF: 0.0153 AC: 923 AN: 60368

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

African (AFR) AF: 0.00296 AC: 123 AN: 41574

American (AMR) AF: 0.00954 AC: 146 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0211 AC: 73 AN: 3466

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5174

South Asian (SAS) AF: 0.0381 AC: 184 AN: 4824

European-Finnish (FIN) AF: 0.00339 AC: 36 AN: 10618

Middle Eastern (MID) AF: 0.0374 AC: 11 AN: 294

European-Non Finnish (NFE) AF: 0.0166 AC: 1129 AN: 68030

Other (OTH) AF: 0.0156 AC: 33 AN: 2114

Alfa AF: 0.0148 Hom.: 76

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

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
1	-	1	Multiple epiphyseal dysplasia type 5 (2)
-	-	2	not provided (2)
-	-	1	Connective tissue disorder (1)
-	-	1	MATN3-related disorder (1)
-	-	1	not specified (1)
-	-	1	Spondyloepimetaphyseal dysplasia, matrilin-3 type;C1846843:Multiple epiphyseal dysplasia type 5;C3887526:Osteoarthritis susceptibility 2 (1)
-	-	-	Osteoarthritis susceptibility 2 (1)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		9.3
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
Mutation Taster		=64/36	polymorphism (auto)

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

Other links and lift over

dbSNP: rs77245812; hg19: chr2-20202930; COSMIC: COSV99067488;