Genetic Variant NM_001393530.1:c.1598G>A (chr20-45293997-C-T) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

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. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

Frequency

Genomes: 𝑓 0.0093 ( 17 hom., cov: 33)

Exomes 𝑓: 0.0010 ( 29 hom. )

Consequence

MATN4
NM_001393530.1 missense

Scores

Clinical Significance

Benign no assertion criteria provided B:1

Conservation

PhyloP100: 3.03

Publications

3 publications found

Variant links:

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]

MATN4 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 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 VariationId is 3041719.Status of the report is no_assertion_criteria_provided, 0 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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 17 AR gene

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MATN4	NM_001393530.1	MANE Select	c.1598G>A	p.Gly533Glu	missense	Exon 9 of 10	NP_001380459.1	O95460-2
MATN4	NM_003833.5		c.1598G>A	p.Gly533Glu	missense	Exon 10 of 11	NP_003824.2
MATN4	NM_001393531.1		c.1598G>A	p.Gly533Glu	missense	Exon 9 of 9	NP_001380460.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MATN4	ENST00000372756.6	TSL:1 MANE Select	c.1598G>A	p.Gly533Glu	missense	Exon 9 of 10	ENSP00000361842.1	O95460-2
MATN4	ENST00000372754.5	TSL:5	c.1721G>A	p.Gly574Glu	missense	Exon 9 of 10	ENSP00000361840.1	O95460-1
MATN4	ENST00000360607.10	TSL:1	c.1475G>A	p.Gly492Glu	missense	Exon 8 of 9	ENSP00000353819.5	O95460-4

Frequencies

GnomAD3 genomes

AF:

0.00930

AC:

1416

AN:

152208

Hom.:

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.00254

AC:

617

AN:

242574

AF XY:

0.00171

show subpopulations

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 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.:

Cov.:

AF XY:

0.000882

AC XY:

637

AN XY:

722038

show subpopulations

African (AFR)

AF:

0.0345

AC:

1153

AN:

33398

American (AMR)

AF:

0.00189

AC:

AN:

44484

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26112

East Asian (EAS)

AF:

0.00

AC:

AN:

39682

South Asian (SAS)

AF:

0.0000464

AC:

AN:

86124

European-Finnish (FIN)

AF:

0.00

AC:

AN:

42600

Middle Eastern (MID)

AF:

0.00121

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.0000720

AC:

AN:

1111728

Other (OTH)

AF:

0.00232

AC:

140

AN:

60296

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

146

220

293

366

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

132

176

220

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00931

AC:

1418

AN:

152326

Hom.:

Cov.:

AF XY:

0.00885

AC XY:

659

AN XY:

74484

show subpopulations

African (AFR)

AF:

0.0324

AC:

1349

AN:

41574

American (AMR)

AF:

0.00288

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.000207

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000118

AC:

AN:

68028

Other (OTH)

AF:

0.00756

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

140

211

281

351

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00369

Hom.:

Bravo

AF:

0.0109

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.0327

AC:

144

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00310

AC:

376

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

ClinVar submissions

Significance:Benign

Revision:no assertion criteria provided

View on ClinVar

Pathogenic

VUS

Benign

Condition

MATN4-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.081

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.34

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.020

Eigen

Benign

0.098

Eigen_PC

Benign

0.19

FATHMM_MKL

Benign

0.50

LIST_S2

Benign

0.83

MetaRNN

Benign

0.0045

MetaSVM

Benign

-0.80

MutationAssessor

Benign

0.98

PhyloP100

3.0

PrimateAI

Uncertain

0.52

PROVEAN

Benign

-0.53

REVEL

Benign

0.10

Sift

Benign

0.12

Sift4G

Benign

0.62

Polyphen

0.028

Vest4

0.14

MVP

0.87

MPC

1.3

ClinPred

0.015

GERP RS

3.4

Varity_R

0.17

gMVP

0.53

Mutation Taster

=98/2

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over