Variant chr2-19993133-T-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_002381.5(MATN3):c.1439A>T(p.Glu480Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,490 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

MATN3
NM_002381.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.03

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:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MATN3	NM_002381.5 linkuse as main transcript	c.1439A>T	p.Glu480Val	missense_variant	8/8	ENST00000407540.8	NP_002372.1
WDR35-DT	NR_110235.1 linkuse as main transcript	n.291+2639T>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MATN3	ENST00000407540.8 linkuse as main transcript	c.1439A>T	p.Glu480Val	missense_variant	8/8	1	NM_002381.5	ENSP00000383894	P1	O15232-1
MATN3	ENST00000421259.2 linkuse as main transcript	c.1313A>T	p.Glu438Val	missense_variant	7/7	1		ENSP00000398753		O15232-2
WDR35-DT	ENST00000416575.2 linkuse as main transcript	n.284+2639T>A		intron_variant, non_coding_transcript_variant		2
WDR35-DT	ENST00000658200.1 linkuse as main transcript	n.286+2639T>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1460490

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726586

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

May 08, 2019

Has not been previously published as pathogenic or benign to our knowledge; Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; In-silico analysis, which includes splice predictors and evolutionary conservation, is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.36

BayesDel_addAF

Uncertain

0.029

BayesDel_noAF

Benign

-0.20

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.12

T;.

Eigen

Uncertain

0.30

Eigen_PC

Uncertain

0.34

FATHMM_MKL

Uncertain

0.81

LIST_S2

Benign

0.63

T;T

M_CAP

Benign

0.034

MetaRNN

Uncertain

0.49

T;T

MetaSVM

Benign

-0.46

MutationAssessor

Uncertain

2.1

M;.

MutationTaster

Benign

0.57

D;N

PrimateAI

Benign

0.40

PROVEAN

Benign

-2.0

N;N

REVEL

Uncertain

0.34

Sift

Pathogenic

0.0

D;D

Sift4G

Uncertain

0.039

D;D

Polyphen

0.91

P;.

Vest4

0.25

MutPred

0.78

Gain of MoRF binding (P = 0.0037);.;

MVP

0.82

MPC

0.55

ClinPred

0.96

GERP RS

4.2

Varity_R

0.30

gMVP

0.70

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over