11-102606646-G-T

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.842C>A(p.Thr281Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.454 in 1,612,304 control chromosomes in the GnomAD database, including 168,687 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.41 ( 13053 hom., cov: 32)

Exomes 𝑓: 0.46 ( 155634 hom. )

Consequence

MMP20
NM_004771.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 0.623

Publications

32 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 Gene-Disease associations (from GenCC):

amelogenesis imperfecta hypomaturation type 2A2
Inheritance: AR Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
amelogenesis imperfecta type 2
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

MMP20 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=2.4934685E-5).

BP6

Variant 11-102606646-G-T is Benign according to our data. Variant chr11-102606646-G-T is described in ClinVar as Benign. ClinVar VariationId is 259542.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.568 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MMP20	NM_004771.4 link	c.842C>A	p.Thr281Asn	missense_variant	Exon 6 of 10	ENST00000260228.3	NP_004762.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MMP20	ENST00000260228.3 link	c.842C>A	p.Thr281Asn	missense_variant	Exon 6 of 10	1	NM_004771.4	ENSP00000260228.2
MMP20	ENST00000544938.1 link	n.298C>A		non_coding_transcript_exon_variant	Exon 3 of 5	3

Frequencies

GnomAD3 genomes

AF:

0.408

AC:

61921

AN:

151858

Hom.:

13040

Cov.:

show subpopulations

Gnomad AFR

AF:

0.308

Gnomad AMI

AF:

0.427

Gnomad AMR

AF:

0.443

Gnomad ASJ

AF:

0.450

Gnomad EAS

AF:

0.454

Gnomad SAS

AF:

0.586

Gnomad FIN

AF:

0.336

Gnomad MID

AF:

0.500

Gnomad NFE

AF:

0.452

Gnomad OTH

AF:

0.442

GnomAD2 exomes

AF:

0.453

AC:

113879

AN:

251412

AF XY:

0.463

show subpopulations

Gnomad AFR exome

AF:

0.302

Gnomad AMR exome

AF:

0.464

Gnomad ASJ exome

AF:

0.462

Gnomad EAS exome

AF:

0.449

Gnomad FIN exome

AF:

0.353

Gnomad NFE exome

AF:

0.456

Gnomad OTH exome

AF:

0.445

GnomAD4 exome

AF:

0.458

AC:

669234

AN:

1460328

Hom.:

155634

Cov.:

AF XY:

0.463

AC XY:

336054

AN XY:

726566

show subpopulations

African (AFR)

AF:

0.295

AC:

9887

AN:

33460

American (AMR)

AF:

0.462

AC:

20652

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.462

AC:

12051

AN:

26112

East Asian (EAS)

AF:

0.436

AC:

17313

AN:

39688

South Asian (SAS)

AF:

0.575

AC:

49531

AN:

86214

European-Finnish (FIN)

AF:

0.357

AC:

19040

AN:

53408

Middle Eastern (MID)

AF:

0.542

AC:

3124

AN:

5766

European-Non Finnish (NFE)

AF:

0.459

AC:

510059

AN:

1110646

Other (OTH)

AF:

0.457

AC:

27577

AN:

60320

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.445

Heterozygous variant carriers

20419

40838

61258

81677

102096

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

15306

30612

45918

61224

76530

<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:

0.408

AC:

61958

AN:

151976

Hom.:

13053

Cov.:

AF XY:

0.406

AC XY:

30144

AN XY:

74312

show subpopulations

African (AFR)

AF:

0.308

AC:

12761

AN:

41462

American (AMR)

AF:

0.443

AC:

6760

AN:

15266

Ashkenazi Jewish (ASJ)

AF:

0.450

AC:

1560

AN:

3468

East Asian (EAS)

AF:

0.454

AC:

2341

AN:

5158

South Asian (SAS)

AF:

0.586

AC:

2828

AN:

4822

European-Finnish (FIN)

AF:

0.336

AC:

3550

AN:

10570

Middle Eastern (MID)

AF:

0.503

AC:

148

AN:

294

European-Non Finnish (NFE)

AF:

0.452

AC:

30676

AN:

67920

Other (OTH)

AF:

0.449

AC:

945

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

1877

3753

5630

7506

9383

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

602

1204

1806

2408

3010

<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:

0.446

Hom.:

47620

Bravo

AF:

0.411

TwinsUK

AF:

0.450

AC:

1667

ALSPAC

AF:

0.467

AC:

1798

ESP6500AA

AF:

0.309

AC:

1360

ESP6500EA

AF:

0.457

AC:

3926

ExAC

AF:

0.452

AC:

54842

Asia WGS

AF:

0.547

AC:

1904

AN:

3478

EpiCase

AF:

0.462

EpiControl

AF:

0.464

ClinVar

Significance: Benign

Submissions summary: Benign:4

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

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Amelogenesis imperfecta hypomaturation type 2A2

Benign:1

Jan 12, 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

0.067

BayesDel_addAF

Benign

-0.81

BayesDel_noAF

Benign

-0.79

CADD

Benign

7.6

(source)

DANN

Benign

0.62

DEOGEN2

Benign

0.078

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.26

LIST_S2

Benign

0.37

MetaRNN

Benign

0.000025

MetaSVM

Benign

-0.92

MutationAssessor

Benign

1.4

PhyloP100

0.62

PrimateAI

Benign

0.27

PROVEAN

Benign

-0.72

REVEL

Benign

0.032

Sift

Benign

0.41

Sift4G

Benign

0.57

Vest4

0.061

ClinPred

0.0095

GERP RS

2.3

Varity_R

0.043

gMVP

0.30

Mutation Taster

=98/2

polymorphism (auto)

(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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over