20-45293944-G-A

Variant names:

• chr20-45293944-G-A
• rs2233105
• NM_001393530.1:c.1651C>T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001393530.1(MATN4):​c.1651C>T​(p.Arg551Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00287 in 1,602,248 control chromosomes in the GnomAD database, including 107 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.014 (51 hom., cov: 32)
  • Exomes 𝑓: 0.0017 (56 hom.)
• Consequence: MATN4 NM_001393530.1 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.94

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0048134327).
• BP6: Variant 20-45293944-G-A is Benign according to our data. Variant chr20-45293944-G-A is described in ClinVar as [Benign]. Clinvar id is 714818.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdExome4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0544 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MATN4	NM_001393530.1	c.1651C>T	p.Arg551Cys	missense_variant	Exon 9 of 10	ENST00000372756.6	NP_001380459.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MATN4	ENST00000372756.6	c.1651C>T	p.Arg551Cys	missense_variant	Exon 9 of 10	1	NM_001393530.1	ENSP00000361842.1
MATN4	ENST00000372754.5	c.1774C>T	p.Arg592Cys	missense_variant	Exon 9 of 10	5		ENSP00000361840.1
MATN4	ENST00000360607.10	c.1528C>T	p.Arg510Cys	missense_variant	Exon 8 of 9	1		ENSP00000353819.5

Frequencies

GnomAD3 genomes AF: 0.0143 AC: 2178 AN: 152206 Hom.: 51 Cov.: 32

Gnomad AFR AF: 0.0491

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00726

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.00908

GnomAD3 exomes AF: 0.00387 AC: 931 AN: 240632 Hom.: 11 AF XY: 0.00282 AC XY: 370 AN XY: 131018

Gnomad AFR exome AF: 0.0510

Gnomad AMR exome AF: 0.00268

Gnomad ASJ exome AF: 0.000101

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000666

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000196

Gnomad OTH exome AF: 0.00219

GnomAD4 exome AF: 0.00166 AC: 2406 AN: 1449924 Hom.: 56 Cov.: 31 AF XY: 0.00145 AC XY: 1048 AN XY: 721900

Gnomad4 AFR exome AF: 0.0566

Gnomad4 AMR exome AF: 0.00360

Gnomad4 ASJ exome AF: 0.000192

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.000117

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000130

Gnomad4 OTH exome AF: 0.00339

GnomAD4 genome AF: 0.0143 AC: 2185 AN: 152324 Hom.: 51 Cov.: 32 AF XY: 0.0139 AC XY: 1034 AN XY: 74492

Gnomad4 AFR AF: 0.0491

Gnomad4 AMR AF: 0.00719

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000147

Gnomad4 OTH AF: 0.00899

Alfa AF: 0.00231 Hom.: 4

Bravo AF: 0.0163

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0445 AC: 196

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00467 AC: 567

Asia WGS AF: 0.00346 AC: 12 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jul 04, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

MATN4-related disorder Benign:1

Jan 02, 2020

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.43
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.015	.;T;.;.;.
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Uncertain	0.93	.;D;D;D;D
MetaRNN	Benign	0.0048	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.6	.;L;.;.;.
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-2.0	N;N;N;N;N
REVEL	Benign	0.17
Sift	Benign	0.073	.;.;T;D;.
Sift4G	Benign	0.085	T;T;T;T;T
Polyphen		0.99	D;.;D;D;D
Vest4		0.36
MVP		0.67
MPC		1.3
ClinPred		0.050	T
GERP RS		3.7
Varity_R		0.58
gMVP		0.43

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs2233105; hg19: chr20-43922584;