NM_002381.5:c.1457G>A

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_002381.5(MATN3):c.1457G>A(p.Arg486His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000323 in 1,612,118 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000032 ( 0 hom. )

Consequence

MATN3
NM_002381.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.374

Variant links:

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]

MATN3 links:

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

WDR35-DT links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.107161105).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MATN3	NM_002381.5 link	c.1457G>A	p.Arg486His	missense_variant	Exon 8 of 8	ENST00000407540.8	NP_002372.1	O15232-1
WDR35-DT	NR_110235.1 link	n.291+2621C>T		intron_variant	Intron 1 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
MATN3	ENST00000407540.8 link	c.1457G>A	p.Arg486His	missense_variant	Exon 8 of 8	1	NM_002381.5	ENSP00000383894.3	O15232-1
MATN3	ENST00000421259.2 link	c.1331G>A	p.Arg444His	missense_variant	Exon 7 of 7	1		ENSP00000398753.2	O15232-2
WDR35-DT	ENST00000416575.2 link	n.284+2621C>T		intron_variant	Intron 1 of 2	2
WDR35-DT	ENST00000658200.1 link	n.286+2621C>T		intron_variant	Intron 1 of 2

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152136

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000282

AC:

AN:

247958

Hom.:

AF XY:

0.0000297

AC XY:

AN XY:

134724

show subpopulations

Gnomad AFR exome

AF:

0.000129

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000357

Gnomad OTH exome

AF:

0.000166

GnomAD4 exome

AF:

0.0000322

AC:

AN:

1459982

Hom.:

Cov.:

AF XY:

0.0000358

AC XY:

AN XY:

726366

show subpopulations

Gnomad4 AFR exome

AF:

0.000120

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000177

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000243

Gnomad4 OTH exome

AF:

0.0000332

GnomAD4 genome

AF:

0.0000329

AC:

AN:

152136

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74314

show subpopulations

Gnomad4 AFR

AF:

0.0000724

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000192

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000282

Hom.:

Bravo

AF:

0.0000302

ExAC

AF:

0.0000166

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Sep 03, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 486 of the MATN3 protein (p.Arg486His). This variant is present in population databases (rs745976322, gnomAD 0.008%). This variant has not been reported in the literature in individuals affected with MATN3-related conditions. An algorithm developed to predict the effect of missense changes on protein structure and function outputs the following: PolyPhen-2: "Probably Damaging". The histidine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.31

CADD

Benign

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.054

T;.

Eigen

Benign

-0.28

Eigen_PC

Benign

-0.12

FATHMM_MKL

Benign

0.15

LIST_S2

Benign

0.82

T;T

M_CAP

Uncertain

0.094

MetaRNN

Benign

0.11

T;T

MetaSVM

Benign

-0.61

MutationAssessor

Benign

1.1

L;.

PrimateAI

Benign

0.23

PROVEAN

Benign

-0.56

N;N

REVEL

Benign

0.27

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

0.035

B;.

Vest4

0.12

MutPred

0.40

Gain of disorder (P = 0.1209);.;

MVP

0.90

MPC

0.83

ClinPred

0.21

GERP RS

4.5

Varity_R

0.20

gMVP

0.50

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over