20-45297933-C-T

Variant names:

• chr20-45297933-C-T
• rs2227275
• NM_001393530.1:c.1564G>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_001393530.1(MATN4):​c.1564G>A​(p.Gly522Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.242 in 1,613,578 control chromosomes in the GnomAD database, including 49,094 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.25 (5015 hom., cov: 32)
  • Exomes 𝑓: 0.24 (44079 hom.)
• Consequence: MATN4 NM_001393530.1 missense
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 1.51
• Publications: 25 publications found

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

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0016362667).
• BP6: Variant 20-45297933-C-T is Benign according to our data. Variant chr20-45297933-C-T is described in ClinVar as Benign. ClinVar VariationId is 3060323.Status of the report is no_assertion_criteria_provided, 0 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.322 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001393530.1. 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
	MATN4	NM_001393530.1	MANE Select	c.1564G>A	p.Gly522Ser	missense	Exon 8 of 10	NP_001380459.1	O95460-2
	MATN4	NM_003833.5		c.1564G>A	p.Gly522Ser	missense	Exon 9 of 11	NP_003824.2
	MATN4	NM_001393531.1		c.1564G>A	p.Gly522Ser	missense	Exon 8 of 9	NP_001380460.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MATN4	ENST00000372756.6	TSL:1 MANE Select	c.1564G>A	p.Gly522Ser	missense	Exon 8 of 10	ENSP00000361842.1	O95460-2
	MATN4	ENST00000372754.5	TSL:5	c.1687G>A	p.Gly563Ser	missense	Exon 8 of 10	ENSP00000361840.1	O95460-1
	MATN4	ENST00000360607.10	TSL:1	c.1441G>A	p.Gly481Ser	missense	Exon 7 of 9	ENSP00000353819.5	O95460-4

Frequencies

GnomAD3 genomes AF: 0.251 AC: 38188 AN: 151984 Hom.: 5002 Cov.: 32

Gnomad AFR AF: 0.255

Gnomad AMI AF: 0.259

Gnomad AMR AF: 0.329

Gnomad ASJ AF: 0.194

Gnomad EAS AF: 0.120

Gnomad SAS AF: 0.122

Gnomad FIN AF: 0.293

Gnomad MID AF: 0.197

Gnomad NFE AF: 0.247

Gnomad OTH AF: 0.251

GnomAD2 exomes AF: 0.235 AC: 59064 AN: 251192 AF XY: 0.227

Gnomad AFR exome AF: 0.249

Gnomad AMR exome AF: 0.327

Gnomad ASJ exome AF: 0.200

Gnomad EAS exome AF: 0.110

Gnomad FIN exome AF: 0.293

Gnomad NFE exome AF: 0.248

Gnomad OTH exome AF: 0.244

GnomAD4 exome AF: 0.241 AC: 352481 AN: 1461476 Hom.: 44079 Cov.: 35 AF XY: 0.237 AC XY: 172496 AN XY: 727070

African (AFR) AF: 0.255 AC: 8531 AN: 33470

American (AMR) AF: 0.331 AC: 14793 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.202 AC: 5291 AN: 26134

East Asian (EAS) AF: 0.137 AC: 5422 AN: 39698

South Asian (SAS) AF: 0.122 AC: 10539 AN: 86248

European-Finnish (FIN) AF: 0.298 AC: 15915 AN: 53394

Middle Eastern (MID) AF: 0.167 AC: 959 AN: 5758

European-Non Finnish (NFE) AF: 0.249 AC: 276819 AN: 1111684

Other (OTH) AF: 0.235 AC: 14212 AN: 60378

GnomAD4 genome AF: 0.251 AC: 38240 AN: 152102 Hom.: 5015 Cov.: 32 AF XY: 0.251 AC XY: 18693 AN XY: 74348

African (AFR) AF: 0.255 AC: 10585 AN: 41506

American (AMR) AF: 0.329 AC: 5034 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.194 AC: 674 AN: 3472

East Asian (EAS) AF: 0.120 AC: 618 AN: 5168

South Asian (SAS) AF: 0.122 AC: 589 AN: 4824

European-Finnish (FIN) AF: 0.293 AC: 3103 AN: 10584

Middle Eastern (MID) AF: 0.212 AC: 62 AN: 292

European-Non Finnish (NFE) AF: 0.247 AC: 16807 AN: 67944

Other (OTH) AF: 0.252 AC: 532 AN: 2110

Alfa AF: 0.242 Hom.: 15767

Bravo AF: 0.256

TwinsUK AF: 0.256 AC: 948

ALSPAC AF: 0.255 AC: 984

ESP6500AA AF: 0.254 AC: 1121

ESP6500EA AF: 0.247 AC: 2126

ExAC AF: 0.230 AC: 27918

Asia WGS AF: 0.145 AC: 505 AN: 3478

EpiCase AF: 0.238

EpiControl AF: 0.235

ClinVar

ClinVar submissions

Significance: Benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	MATN4-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	18
DANN	Benign	0.97
DEOGEN2	Benign	0.0012	T
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.037
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.66	T
MetaRNN	Benign	0.0016	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.85	L
PhyloP100		1.5
PrimateAI	Benign	0.44	T
PROVEAN	Benign	0.47	N
REVEL	Benign	0.15
Sift	Benign	0.62	T
Sift4G	Benign	0.74	T
Polyphen		0.046	B
Vest4		0.19
MPC		0.50
ClinPred		0.0041	T
GERP RS		4.6
Varity_R		0.15
gMVP		0.52
Mutation Taster		=97/3	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2227275; hg19: chr20-43926573; COSMIC: COSV61351665;