rs730882210

Positions:

• chr20-45304356-C-G

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_001393530.1(MATN4):​c.515G>C​(p.Gly172Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MATN4 NM_001393530.1 missense
• Clinical Significance: Likely pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.89

Genes affected

MATN4 (HGNC:6910): (matrilin 4) This gene encodes a member of von Willebrand factor A domain-containing protein family. The proteins of this family are thought to be involved in the formation of filamentous networks in the extracellular matrices of various tissues. This family member is thought to be play a role in reorganizing and regenerating the corneal matrix in granular and lattice type I dystrophies. It may also be involved in wound healing in the dentin-pulp complex. Alternative splicing results in multiple transcript variants. [provided by RefSeq, May 2013]

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.976
• PP5: Variant 20-45304356-C-G is Pathogenic according to our data. Variant chr20-45304356-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 183295.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr20-45304356-C-G is described in Lovd as [Likely_pathogenic]. Variant chr20-45304356-C-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MATN4	NM_001393530.1	c.515G>C	p.Gly172Ala	missense_variant	3/10	ENST00000372756.6	NP_001380459.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MATN4	ENST00000372756.6	c.515G>C	p.Gly172Ala	missense_variant	3/10	1	NM_001393530.1	ENSP00000361842.1
MATN4	ENST00000372754.5	c.515G>C	p.Gly172Ala	missense_variant	2/10	5		ENSP00000361840.1
MATN4	ENST00000360607.10	c.515G>C	p.Gly172Ala	missense_variant	3/9	1		ENSP00000353819.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Diabetes insipidus;C0015300:Proptosis;C0036572:Seizure;C0079541:Holoprosencephaly sequence;C0557874:Global developmental delay;C4551563:Microcephaly;CN228305:Lumbosacral myelomeningocele Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center

Dec 01, 2014

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.71
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.44
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Benign	0.098	.;T;.;.;.
Eigen	Uncertain	0.67
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	.;D;D;D;D
M_CAP	Pathogenic	0.45	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D
MetaSVM	Uncertain	0.79	D
MutationAssessor	Uncertain	2.6	M;M;M;.;M
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-5.4	D;D;D;D;D
REVEL	Pathogenic	0.98
Sift	Pathogenic	0.0	.;.;D;D;.
Sift4G	Pathogenic	0.0	D;D;D;D;D
Polyphen		1.0	D;.;D;D;D
Vest4		0.95
MutPred		0.90		Gain of catalytic residue at G172 (P = 0.0688);Gain of catalytic residue at G172 (P = 0.0688);Gain of catalytic residue at G172 (P = 0.0688);Gain of catalytic residue at G172 (P = 0.0688);Gain of catalytic residue at G172 (P = 0.0688);
MVP		0.97
MPC		1.3
ClinPred		1.0	D
GERP RS		3.8
Varity_R		0.92
gMVP		0.95

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

Other links and lift over

dbSNP: rs730882210; hg19: chr20-43932996;