NM_002381.5:c.911G>C

Variant names:

• chr2-20003166-C-G
• rs1265804493
• NM_002381.5:c.911G>C
• MATN3 p.Cys304Ser

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PS1 PM2 PP3_Strong

The NM_002381.5(MATN3):​c.911G>C​(p.Cys304Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,642 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: MATN3 NM_002381.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.36
• 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: Pathogenic. The variant received 10 ACMG points.

• PS1: Transcript NM_002381.5 (MATN3) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.993

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.911G>C	p.Cys304Ser	missense	Exon 3 of 8	NP_002372.1	O15232-1
	WDR35-DT	NR_110235.1		n.364-854C>G		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MATN3	ENST00000407540.8	TSL:1 MANE Select	c.911G>C	p.Cys304Ser	missense	Exon 3 of 8	ENSP00000383894.3	O15232-1
	MATN3	ENST00000421259.2	TSL:1	c.791-1086G>C		intron	N/A	ENSP00000398753.2	O15232-2
	MATN3	ENST00000856777.1		c.911G>C	p.Cys304Ser	missense	Exon 3 of 8	ENSP00000526836.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461642 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 727104

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53394

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111824

Other (OTH) AF: 0.00 AC: 0 AN: 60370

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.48
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.88	D
Eigen	Pathogenic	0.96
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.89	D
M_CAP	Uncertain	0.20	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.8	H
PhyloP100		7.4
PrimateAI	Uncertain	0.58	T
PROVEAN	Pathogenic	-9.2	D
REVEL	Pathogenic	0.88
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Varity_R		0.98
gMVP		0.99
Mutation Taster		=10/90	disease causing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs1265804493;

hg19: chr2-20202927;