rs370798785

Variant names:

• chr2-19993116-G-A
• rs370798785
• NM_002381.5:c.1456C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_002381.5(MATN3):​c.1456C>T​(p.Arg486Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000347 in 1,612,026 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R486H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000032 (0 hom.)
• Consequence: MATN3 NM_002381.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 2.48
• Publications: 0 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: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.13258603).

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.1456C>T	p.Arg486Cys	missense	Exon 8 of 8	NP_002372.1	O15232-1
	WDR35-DT	NR_110235.1		n.291+2622G>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.1456C>T	p.Arg486Cys	missense	Exon 8 of 8	ENSP00000383894.3	O15232-1
	MATN3	ENST00000421259.2	TSL:1	c.1330C>T	p.Arg444Cys	missense	Exon 7 of 7	ENSP00000398753.2	O15232-2
	MATN3	ENST00000856777.1		c.1450C>T	p.Arg484Cys	missense	Exon 8 of 8	ENSP00000526836.1

Frequencies

GnomAD3 genomes AF: 0.0000657 AC: 10 AN: 152130 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000565 AC: 14 AN: 247940 AF XY: 0.0000445

Gnomad AFR exome AF: 0.000194

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000111

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000715

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000315 AC: 46 AN: 1459896 Hom.: 0 Cov.: 29 AF XY: 0.0000303 AC XY: 22 AN XY: 726356

African (AFR) AF: 0.0000898 AC: 3 AN: 33426

American (AMR) AF: 0.0000224 AC: 1 AN: 44668

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26110

East Asian (EAS) AF: 0.0000758 AC: 3 AN: 39592

South Asian (SAS) AF: 0.00 AC: 0 AN: 86180

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53316

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.0000351 AC: 39 AN: 1110542

Other (OTH) AF: 0.00 AC: 0 AN: 60302

GnomAD4 genome AF: 0.0000657 AC: 10 AN: 152130 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74308

African (AFR) AF: 0.000169 AC: 7 AN: 41440

American (AMR) AF: 0.00 AC: 0 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.000192 AC: 1 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10584

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68014

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.0000775 Hom.: 0

Bravo AF: 0.0000869

ESP6500AA AF: 0.000270 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000828 AC: 10

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.16
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.046	T
Eigen	Benign	-0.18
Eigen_PC	Benign	-0.014
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.86	D
M_CAP	Uncertain	0.20	D
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-0.61	T
MutationAssessor	Benign	1.8	L
PhyloP100		2.5
PrimateAI	Benign	0.26	T
PROVEAN	Benign	0.50	N
REVEL	Uncertain	0.29
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.078	B
Vest4		0.30
MVP		0.89
MPC		0.87
ClinPred		0.15	T
GERP RS		3.5
Varity_R		0.11
gMVP		0.60
Mutation Taster		=84/16	polymorphism

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: rs370798785; hg19: chr2-20192877;