chr2-20005780-C-T

Position:

chr2-20005780-C-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBS1BS2

The NM_002381.5(MATN3):c.754G>A(p.Glu252Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0268 in 1,605,932 control chromosomes in the GnomAD database, including 714 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.019 ( 40 hom., cov: 33)

Exomes 𝑓: 0.028 ( 674 hom. )

Consequence

MATN3
NM_002381.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 3.42

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -18 ACMG points.

PM1

In a domain VWFA (size 175) in uniprot entity MATN3_HUMAN there are 27 pathogenic changes around while only 1 benign (96%) in NM_002381.5

BP4

Computational evidence support a benign effect (MetaRNN=0.008475125).

BP6

Variant 2-20005780-C-T is Benign according to our data. Variant chr2-20005780-C-T is described in ClinVar as [Benign]. Clinvar id is 258648.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-20005780-C-T is described in Lovd as [Benign]. Variant chr2-20005780-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0194 (2959/152282) while in subpopulation SAS AF= 0.0413 (199/4816). AF 95% confidence interval is 0.0366. There are 40 homozygotes in gnomad4. There are 1471 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 40 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MATN3	NM_002381.5 linkuse as main transcript	c.754G>A	p.Glu252Lys	missense_variant	2/8	ENST00000407540.8	NP_002372.1	O15232-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MATN3	ENST00000407540.8 linkuse as main transcript	c.754G>A	p.Glu252Lys	missense_variant	2/8	1	NM_002381.5	ENSP00000383894.3		O15232-1
MATN3	ENST00000421259.2 linkuse as main transcript	c.754G>A	p.Glu252Lys	missense_variant	2/7	1		ENSP00000398753.2		O15232-2

Frequencies

GnomAD3 genomes

AF:

0.0194

AC:

2959

AN:

152164

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00478

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0154

Gnomad ASJ

AF:

0.0176

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.0415

Gnomad FIN

AF:

0.0211

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.0291

Gnomad OTH

AF:

0.0254

GnomAD3 exomes

AF:

0.0227

AC:

5472

AN:

241386

Hom.:

104

AF XY:

0.0251

AC XY:

3278

AN XY:

130654

show subpopulations

Gnomad AFR exome

AF:

0.00490

Gnomad AMR exome

AF:

0.0104

Gnomad ASJ exome

AF:

0.0160

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0439

Gnomad FIN exome

AF:

0.0201

Gnomad NFE exome

AF:

0.0280

Gnomad OTH exome

AF:

0.0228

GnomAD4 exome

AF:

0.0275

AC:

40010

AN:

1453650

Hom.:

674

Cov.:

AF XY:

0.0286

AC XY:

20625

AN XY:

721630

show subpopulations

Gnomad4 AFR exome

AF:

0.00375

Gnomad4 AMR exome

AF:

0.0109

Gnomad4 ASJ exome

AF:

0.0164

Gnomad4 EAS exome

AF:

0.0000506

Gnomad4 SAS exome

AF:

0.0449

Gnomad4 FIN exome

AF:

0.0196

Gnomad4 NFE exome

AF:

0.0293

Gnomad4 OTH exome

AF:

0.0248

GnomAD4 genome

AF:

0.0194

AC:

2959

AN:

152282

Hom.:

Cov.:

AF XY:

0.0198

AC XY:

1471

AN XY:

74456

show subpopulations

Gnomad4 AFR

AF:

0.00477

Gnomad4 AMR

AF:

0.0154

Gnomad4 ASJ

AF:

0.0176

Gnomad4 EAS

AF:

0.000386

Gnomad4 SAS

AF:

0.0413

Gnomad4 FIN

AF:

0.0211

Gnomad4 NFE

AF:

0.0291

Gnomad4 OTH

AF:

0.0251

Alfa

AF:

0.0259

Hom.:

Bravo

AF:

0.0178

TwinsUK

AF:

0.0289

AC:

107

ALSPAC

AF:

0.0283

AC:

109

ESP6500AA

AF:

0.00624

AC:

ESP6500EA

AF:

0.0280

AC:

232

ExAC

AF:

0.0228

AC:

2755

Asia WGS

AF:

0.0160

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

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)	Oct 06, 2017	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 26, 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. -

Connective tissue disorder

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

May 12, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.56

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.15

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.39

T;.

Eigen

Uncertain

0.62

Eigen_PC

Uncertain

0.62

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.96

D;D

MetaRNN

Benign

0.0085

T;T

MetaSVM

Uncertain

-0.27

MutationAssessor

Benign

1.8

L;L

PrimateAI

Uncertain

0.62

PROVEAN

Uncertain

-2.9

D;D

REVEL

Uncertain

0.34

Sift

Uncertain

0.0050

D;D

Sift4G

Uncertain

0.0030

D;D

Polyphen

1.0

D;.

Vest4

0.44

MPC

0.79

ClinPred

0.013

GERP RS

5.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.74

gMVP

0.93

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