11-102606578-C-T

Variant names:

• chr11-102606578-C-T
• rs148818720
• NM_004771.4:c.910G>A

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_Moderate BS1_Supporting BS2

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
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• 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]

ACMG classification

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

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MMP20	NM_004771.4	c.910G>A	p.Ala304Thr	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	c.910G>A	p.Ala304Thr	missense_variant	Exon 6 of 10	1	NM_004771.4	ENSP00000260228.2
MMP20	ENST00000544938.1	n.366G>A		non_coding_transcript_exon_variant	Exon 3 of 5	3

Frequencies

GnomAD3 genomes AF: 0.00169 AC: 257 AN: 152120 Hom.: 0 Cov.: 32

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.: 0 AF XY: 0.00152 AC XY: 207 AN XY: 135848

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.: 3 Cov.: 31 AF XY: 0.00241 AC XY: 1754 AN XY: 727162

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.: 0 Cov.: 32 AF XY: 0.00144 AC XY: 107 AN XY: 74446

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.: 0

Bravo AF: 0.00171

TwinsUK AF: 0.00189 AC: 7

ALSPAC AF: 0.00234 AC: 9

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00291 AC: 25

ExAC AF: 0.00142 AC: 172

Asia WGS AF: 0.000866 AC: 3 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

Submissions by phenotype

not provided Uncertain:1

Sep 30, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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	T
BayesDel_noAF	Uncertain	0.010
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.24	T
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.81	T
M_CAP	Benign	0.052	D
MetaRNN	Benign	0.10	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Uncertain	2.4	M
PrimateAI	Benign	0.48	T
PROVEAN	Uncertain	-3.6	D
REVEL	Uncertain	0.33
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.73
MVP		0.69
MPC		0.26
ClinPred		0.040	T
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

Other links and lift over

dbSNP: rs148818720; hg19: chr11-102477309; COSMIC: COSV52774709; COSMIC: COSV52774709;