20-45293997-C-T

Position:

• chr20-45293997-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001393530.1(MATN4):​c.1598G>A​(p.Gly533Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0018 in 1,602,514 control chromosomes in the GnomAD database, including 46 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0093 (17 hom., cov: 33)
  • Exomes 𝑓: 0.0010 (29 hom.)
• Consequence: MATN4 NM_001393530.1 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 3.03

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0044611692).
• BP6: Variant 20-45293997-C-T is Benign according to our data. Variant chr20-45293997-C-T is described in ClinVar as [Benign]. Clinvar id is 3041719.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00931 (1418/152326) while in subpopulation AFR AF= 0.0324 (1349/41574). AF 95% confidence interval is 0.031. There are 17 homozygotes in gnomad4. There are 659 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 17 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MATN4	NM_001393530.1	c.1598G>A	p.Gly533Glu	missense_variant	9/10	ENST00000372756.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MATN4	ENST00000372756.6	c.1598G>A	p.Gly533Glu	missense_variant	9/10	1	NM_001393530.1

Frequencies

GnomAD3 genomes AF: 0.00930 AC: 1416 AN: 152208 Hom.: 17 Cov.: 33

Gnomad AFR AF: 0.0325

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00288

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00764

GnomAD3 exomes AF: 0.00254 AC: 617 AN: 242574 Hom.: 12 AF XY: 0.00171 AC XY: 226 AN XY: 132072

Gnomad AFR exome AF: 0.0338

Gnomad AMR exome AF: 0.00169

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000328

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000707

Gnomad OTH exome AF: 0.000660

GnomAD4 exome AF: 0.00101 AC: 1469 AN: 1450188 Hom.: 29 Cov.: 31 AF XY: 0.000882 AC XY: 637 AN XY: 722038

Gnomad4 AFR exome AF: 0.0345

Gnomad4 AMR exome AF: 0.00189

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000720

Gnomad4 OTH exome AF: 0.00232

GnomAD4 genome AF: 0.00931 AC: 1418 AN: 152326 Hom.: 17 Cov.: 33 AF XY: 0.00885 AC XY: 659 AN XY: 74484

Gnomad4 AFR AF: 0.0324

Gnomad4 AMR AF: 0.00288

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000118

Gnomad4 OTH AF: 0.00756

Alfa AF: 0.00166 Hom.: 9

Bravo AF: 0.0109

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.0327 AC: 144

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00310 AC: 376

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

MATN4-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 08, 2019

This variant is classified as 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	0.081
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	21
DANN	Uncertain	0.99
Eigen	Benign	0.098
Eigen_PC	Benign	0.19
FATHMM_MKL	Benign	0.50	D
MetaRNN	Benign	0.0045	T;T;T;T;T
MetaSVM	Benign	-0.80	T
MutationTaster	Benign	0.94	N;N;N;N;N;N;N;N
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-0.53	N;N;N;N;N
REVEL	Benign	0.10
Sift4G	Benign	0.62	T;T;T;T;T
Polyphen		0.028	B;.;D;B;B
Vest4		0.14
MVP		0.87
MPC		1.3
ClinPred		0.015	T
GERP RS		3.4
Varity_R		0.17
gMVP		0.53

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: rs79708482; hg19: chr20-43922637;