11-102606578-C-T
Variant names:
Variant summary
Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_ModerateBS1_SupportingBS2
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 (★★).
Frequency
Genomes: 𝑓 0.0017 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0024 ( 3 hom. )
Consequence
MMP20
NM_004771.4 missense
NM_004771.4 missense
Scores
2
9
8
Clinical Significance
Conservation
PhyloP100: 2.37
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]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -7 ACMG points.
BP4
Computational evidence support a benign effect (MetaRNN=0.1004149).
BS1
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00169 (257/152238) while in subpopulation NFE AF= 0.00272 (185/68014). AF 95% confidence interval is 0.0024. There are 0 homozygotes in gnomad4. There are 107 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
BS2
High Homozygotes in GnomAdExome4 at 3 AR gene
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00169 AC: 257AN: 152120Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00156 AC: 393AN: 251322Hom.: 0 AF XY: 0.00152 AC XY: 207AN XY: 135848
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GnomAD4 exome AF: 0.00240 AC: 3515AN: 1461730Hom.: 3 Cov.: 31 AF XY: 0.00241 AC XY: 1754AN XY: 727162
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GnomAD4 genome AF: 0.00169 AC: 257AN: 152238Hom.: 0 Cov.: 32 AF XY: 0.00144 AC XY: 107AN XY: 74446
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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:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
CADD
Uncertain
DANN
Pathogenic
DEOGEN2
Benign
T
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T
M_CAP
Benign
D
MetaRNN
Benign
T
MetaSVM
Benign
T
MutationAssessor
Uncertain
M
PrimateAI
Benign
T
PROVEAN
Uncertain
D
REVEL
Uncertain
Sift
Uncertain
D
Sift4G
Uncertain
D
Polyphen
D
Vest4
MVP
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at