11-102611773-T-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_004771.4(MMP20):c.505A>C(p.Ile169Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00765 in 1,614,134 control chromosomes in the GnomAD database, including 262 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 (★★).

Frequency

Genomes: 𝑓 0.0095 ( 25 hom., cov: 33)

Exomes 𝑓: 0.0075 ( 237 hom. )

Consequence

MMP20
NM_004771.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 1.73

Publications

14 publications found

Variant links:

Genes affected

MMP20 (HGNC:7167): (matrix metallopeptidase 20) Proteins of the matrix metalloproteinase (MMP) family are involved in the breakdown of extracellular matrix in normal physiological processes, such as embryonic development, reproduction, and tissue remodeling, as well as in disease processes, such as arthritis and metastasis. Most MMP's are secreted as inactive proproteins which are activated when cleaved by extracellular proteinases. The protein encoded by this gene degrades amelogenin, the major protein component of dental enamel matrix, and thus thought to play a role in tooth enamel formation. A mutation in this gene, which alters the normal splice pattern and results in premature termination of the encoded protein, has been associated with amelogenesis imperfecta. This gene is part of a cluster of MMP genes located on chromosome 11q22.3. [provided by RefSeq, Aug 2011]

MMP20 links:

MMP20-AS1 (HGNC:56362): (MMP20 antisense RNA 1)

MMP20-AS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0022335649).

BP6

Variant 11-102611773-T-G is Benign according to our data. Variant chr11-102611773-T-G is described in ClinVar as Benign. ClinVar VariationId is 301949.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0756 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MMP20	NM_004771.4 link	c.505A>C	p.Ile169Leu	missense_variant	Exon 3 of 10	ENST00000260228.3	NP_004762.2	O60882

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
MMP20	ENST00000260228.3 link	c.505A>C	p.Ile169Leu	missense_variant	Exon 3 of 10	1	NM_004771.4	ENSP00000260228.2	O60882
MMP20-AS1	ENST00000542119.2 link	n.233+4321T>G		intron_variant	Intron 1 of 3	3
MMP20-AS1	ENST00000782665.1 link	n.233+4321T>G		intron_variant	Intron 1 of 5

Frequencies

GnomAD3 genomes

AF:

0.00949

AC:

1444

AN:

152204

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0124

Gnomad AMI

AF:

0.0373

Gnomad AMR

AF:

0.00464

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.0817

Gnomad SAS

AF:

0.0288

Gnomad FIN

AF:

0.000282

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00350

Gnomad OTH

AF:

0.00861

GnomAD2 exomes

AF:

0.0128

AC:

3218

AN:

251360

AF XY:

0.0135

show subpopulations

Gnomad AFR exome

AF:

0.0110

Gnomad AMR exome

AF:

0.00237

Gnomad ASJ exome

AF:

0.0000992

Gnomad EAS exome

AF:

0.0922

Gnomad FIN exome

AF:

0.000185

Gnomad NFE exome

AF:

0.00325

Gnomad OTH exome

AF:

0.00766

GnomAD4 exome

AF:

0.00747

AC:

10913

AN:

1461812

Hom.:

237

Cov.:

AF XY:

0.00808

AC XY:

5878

AN XY:

727222

show subpopulations

African (AFR)

AF:

0.0120

AC:

402

AN:

33480

American (AMR)

AF:

0.00277

AC:

124

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.000230

AC:

AN:

26136

East Asian (EAS)

AF:

0.0832

AC:

3301

AN:

39698

South Asian (SAS)

AF:

0.0288

AC:

2486

AN:

86258

European-Finnish (FIN)

AF:

0.000150

AC:

AN:

53362

Middle Eastern (MID)

AF:

0.00780

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00364

AC:

4043

AN:

1111994

Other (OTH)

AF:

0.00825

AC:

498

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

621

1242

1864

2485

3106

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

228

456

684

912

1140

<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:

0.00947

AC:

1442

AN:

152322

Hom.:

Cov.:

AF XY:

0.0100

AC XY:

748

AN XY:

74506

show subpopulations

African (AFR)

AF:

0.0124

AC:

514

AN:

41570

American (AMR)

AF:

0.00464

AC:

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3468

East Asian (EAS)

AF:

0.0821

AC:

425

AN:

5178

South Asian (SAS)

AF:

0.0284

AC:

137

AN:

4830

European-Finnish (FIN)

AF:

0.000282

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00350

AC:

238

AN:

68028

Other (OTH)

AF:

0.00805

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

136

203

271

339

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:

0.00750

Hom.:

Bravo

AF:

0.0104

TwinsUK

AF:

0.00485

AC:

ALSPAC

AF:

0.00597

AC:

ESP6500AA

AF:

0.0118

AC:

ESP6500EA

AF:

0.00395

AC:

ExAC

AF:

0.0132

AC:

1602

Asia WGS

AF:

0.0350

AC:

121

AN:

3478

EpiCase

AF:

0.00480

EpiControl

AF:

0.00261

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Nov 12, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Amelogenesis imperfecta hypomaturation type 2A2

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.32

BayesDel_addAF

Benign

-0.57

BayesDel_noAF

Benign

-0.52

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.10

Eigen

Benign

-0.23

Eigen_PC

Benign

-0.17

FATHMM_MKL

Benign

0.71

LIST_S2

Uncertain

0.88

MetaRNN

Benign

0.0022

MetaSVM

Benign

-1.0

MutationAssessor

Benign

2.0

PhyloP100

1.7

PrimateAI

Benign

0.47

PROVEAN

Benign

-1.9

REVEL

Benign

0.10

Sift

Uncertain

0.0030

Sift4G

Uncertain

0.051

Polyphen

0.0030

Vest4

0.14

MutPred

0.74

Gain of sheet (P = 0.1451);

MPC

0.096

ClinPred

0.038

GERP RS

1.8

Varity_R

0.62

gMVP

0.74

Mutation Taster

=88/12

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over