rs1784423

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_004771.4(MMP20):c.824T>C(p.Val275Ala) 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 1,611,858 control chromosomes in the GnomAD database, including 168,714 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.41 ( 13093 hom., cov: 32)

Exomes 𝑓: 0.46 ( 155621 hom. )

Consequence

MMP20
NM_004771.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.748

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=1.6944017E-5).

BP6

Variant 11-102606664-A-G is Benign according to our data. Variant chr11-102606664-A-G is described in ClinVar as [Benign]. Clinvar id is 259541.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-102606664-A-G is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.569 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MMP20	NM_004771.4 linkuse as main transcript	c.824T>C	p.Val275Ala	missense_variant	6/10	ENST00000260228.3	NP_004762.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MMP20	ENST00000260228.3 linkuse as main transcript	c.824T>C	p.Val275Ala	missense_variant	6/10	1	NM_004771.4	ENSP00000260228	P1
MMP20	ENST00000544938.1 linkuse as main transcript	n.280T>C		non_coding_transcript_exon_variant	3/5	3

Frequencies

GnomAD3 genomes

AF:

0.408

AC:

61992

AN:

151872

Hom.:

13080

Cov.:

show subpopulations

Gnomad AFR

AF:

0.309

Gnomad AMI

AF:

0.428

Gnomad AMR

AF:

0.443

Gnomad ASJ

AF:

0.450

Gnomad EAS

AF:

0.455

Gnomad SAS

AF:

0.586

Gnomad FIN

AF:

0.336

Gnomad MID

AF:

0.500

Gnomad NFE

AF:

0.452

Gnomad OTH

AF:

0.443

GnomAD3 exomes

AF:

0.453

AC:

113885

AN:

251382

Hom.:

26455

AF XY:

0.463

AC XY:

62925

AN XY:

135874

show subpopulations

Gnomad AFR exome

AF:

0.302

Gnomad AMR exome

AF:

0.464

Gnomad ASJ exome

AF:

0.462

Gnomad EAS exome

AF:

0.450

Gnomad SAS exome

AF:

0.582

Gnomad FIN exome

AF:

0.353

Gnomad NFE exome

AF:

0.456

Gnomad OTH exome

AF:

0.445

GnomAD4 exome

AF:

0.458

AC:

669014

AN:

1459868

Hom.:

155621

Cov.:

AF XY:

0.463

AC XY:

335945

AN XY:

726334

show subpopulations

Gnomad4 AFR exome

AF:

0.296

Gnomad4 AMR exome

AF:

0.462

Gnomad4 ASJ exome

AF:

0.462

Gnomad4 EAS exome

AF:

0.436

Gnomad4 SAS exome

AF:

0.575

Gnomad4 FIN exome

AF:

0.357

Gnomad4 NFE exome

AF:

0.459

Gnomad4 OTH exome

AF:

0.457

GnomAD4 genome

AF:

0.408

AC:

62029

AN:

151990

Hom.:

13093

Cov.:

AF XY:

0.406

AC XY:

30172

AN XY:

74310

show subpopulations

Gnomad4 AFR

AF:

0.308

Gnomad4 AMR

AF:

0.443

Gnomad4 ASJ

AF:

0.450

Gnomad4 EAS

AF:

0.455

Gnomad4 SAS

AF:

0.587

Gnomad4 FIN

AF:

0.336

Gnomad4 NFE

AF:

0.452

Gnomad4 OTH

AF:

0.450

Alfa

AF:

0.453

Hom.:

34364

Bravo

AF:

0.411

TwinsUK

AF:

0.450

AC:

1668

ALSPAC

AF:

0.467

AC:

1800

ESP6500AA

AF:

0.308

AC:

1359

ESP6500EA

AF:

0.457

AC:

3927

ExAC

AF:

0.452

AC:

54856

Asia WGS

AF:

0.548

AC:

1906

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

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 12, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

- -

Amelogenesis imperfecta hypomaturation type 2A2

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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

0.062

BayesDel_addAF

Benign

-0.82

BayesDel_noAF

Benign

-0.80

CADD

Benign

DANN

Benign

0.56

DEOGEN2

Benign

0.031

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.0016

LIST_S2

Benign

0.017

MetaRNN

Benign

0.000017

MetaSVM

Benign

-0.93

MutationAssessor

Benign

-1.3

MutationTaster

Benign

1.0

PrimateAI

Benign

0.26

PROVEAN

Benign

0.36

REVEL

Benign

0.096

Sift

Benign

1.0

Sift4G

Benign

0.82

Polyphen

0.0

Vest4

0.011

MPC

0.039

ClinPred

0.0068

GERP RS

4.5

Varity_R

0.031

gMVP

0.26

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over