11-102606578-C-T

Position:

chr11-102606578-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_004771.4(MMP20):c.910G>A(p.Ala304Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00234 in 1,613,968 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A304G) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0017 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0024 ( 3 hom. )

Consequence

MMP20
NM_004771.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 2.37

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 Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.1004149).

BS2

High Homozygotes in GnomAdExome4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MMP20	NM_004771.4 linkuse as main transcript	c.910G>A	p.Ala304Thr	missense_variant	6/10	ENST00000260228.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MMP20	ENST00000260228.3 linkuse as main transcript	c.910G>A	p.Ala304Thr	missense_variant	6/10	1	NM_004771.4	P1
MMP20	ENST00000544938.1 linkuse as main transcript	n.366G>A		non_coding_transcript_exon_variant	3/5	3

Frequencies

GnomAD3 genomes

AF:

0.00169

AC:

257

AN:

152120

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000821

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00118

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000770

Gnomad SAS

AF:

0.00166

Gnomad FIN

AF:

0.000377

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00272

Gnomad OTH

AF:

0.00191

GnomAD3 exomes

AF:

0.00156

AC:

393

AN:

251322

Hom.:

AF XY:

0.00152

AC XY:

207

AN XY:

135848

show subpopulations

Gnomad AFR exome

AF:

0.000369

Gnomad AMR exome

AF:

0.00113

Gnomad ASJ exome

AF:

0.000298

Gnomad EAS exome

AF:

0.000489

Gnomad SAS exome

AF:

0.00183

Gnomad FIN exome

AF:

0.000139

Gnomad NFE exome

AF:

0.00231

Gnomad OTH exome

AF:

0.00228

GnomAD4 exome

AF:

0.00240

AC:

3515

AN:

1461730

Hom.:

Cov.:

AF XY:

0.00241

AC XY:

1754

AN XY:

727162

show subpopulations

Gnomad4 AFR exome

AF:

0.000418

Gnomad4 AMR exome

AF:

0.00114

Gnomad4 ASJ exome

AF:

0.000153

Gnomad4 EAS exome

AF:

0.000479

Gnomad4 SAS exome

AF:

0.00167

Gnomad4 FIN exome

AF:

0.000206

Gnomad4 NFE exome

AF:

0.00281

Gnomad4 OTH exome

AF:

0.00232

GnomAD4 genome

AF:

0.00169

AC:

257

AN:

152238

Hom.:

Cov.:

AF XY:

0.00144

AC XY:

107

AN XY:

74446

show subpopulations

Gnomad4 AFR

AF:

0.000818

Gnomad4 AMR

AF:

0.00118

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000772

Gnomad4 SAS

AF:

0.00166

Gnomad4 FIN

AF:

0.000377

Gnomad4 NFE

AF:

0.00272

Gnomad4 OTH

AF:

0.00189

Alfa

AF:

0.00209

Hom.:

Bravo

AF:

0.00171

TwinsUK

AF:

0.00189

AC:

ALSPAC

AF:

0.00234

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00291

AC:

ExAC

AF:

0.00142

AC:

172

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.00218

EpiControl

AF:

0.00273

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 30, 2021

This sequence change replaces alanine with threonine at codon 304 of the MMP20 protein (p.Ala304Thr). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and threonine. This variant is present in population databases (rs148818720, ExAC 0.2%). This variant has been observed in individual(s) with melogenesis imperfecta (PMID: 19966041). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 301942). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). Experimental studies have shown that this variant affects MMP20 function (PMID: 19966041). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Amelogenesis imperfecta hypomaturation type 2A2

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

The MMP20 c.910G>A (p.Ala304Thr) missense variant has been reported in a single case study in which it was found in a homozygous state in two siblings whose parents were both heterozygous carriers of the variant (Lee et al. 2010). In vitro functional experiments showed that this variant produces a protein that is catalytically active, but has decreased expression compared to wild type MMP20. The p.Ala304Thr variant was absent from 100 controls and is reported at a frequency of 0.00298 in the European population of the 1000 Genomes Project. The evidence for this variant is limited. The p.Ala304Thr variant is therefore classified as a variant of unknown significance but suspicious for pathogenicity for amelogenesis imperfecta. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.74

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Uncertain

0.010

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.24

Eigen

Uncertain

0.55

Eigen_PC

Uncertain

0.51

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.81

M_CAP

Benign

0.052

MetaRNN

Benign

0.10

MetaSVM

Benign

-0.90

MutationAssessor

Uncertain

2.4

MutationTaster

Benign

1.0

PrimateAI

Benign

0.48

PROVEAN

Uncertain

-3.6

REVEL

Uncertain

0.33

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.0020

Polyphen

1.0

Vest4

0.73

MVP

0.69

MPC

0.26

ClinPred

0.040

GERP RS

5.5

Varity_R

0.68

gMVP

0.84

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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