chr11-102594759-T-A

Position:

chr11-102594759-T-A

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong

The NM_004771.4(MMP20):c.954-2A>T variant causes a splice acceptor, intron change. The variant allele was found at a frequency of 0.00215 in 1,550,600 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: 𝑓 0.0022 ( 1 hom., cov: 26)

Exomes 𝑓: 0.0021 ( 4 hom. )

Consequence

MMP20
NM_004771.4 splice_acceptor, intron

Scores

Splicing: ADA: 1.000

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:8

Conservation

PhyloP100: 4.96

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:

MMP20 (HGNC:):

MMP20 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.

PP5

Variant 11-102594759-T-A is Pathogenic according to our data. Variant chr11-102594759-T-A is described in ClinVar as [Pathogenic]. Clinvar id is 5428.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-102594759-T-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MMP20	NM_004771.4 linkuse as main transcript	c.954-2A>T		splice_acceptor_variant, intron_variant		ENST00000260228.3	NP_004762.2	O60882

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MMP20	ENST00000260228.3 linkuse as main transcript	c.954-2A>T		splice_acceptor_variant, intron_variant		1	NM_004771.4	ENSP00000260228.2		O60882
MMP20	ENST00000544938.1 linkuse as main transcript	n.593-2A>T		splice_acceptor_variant, intron_variant		3

Frequencies

GnomAD3 genomes

AF:

0.00221

AC:

236

AN:

106738

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000535

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00786

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000196

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00256

Gnomad OTH

AF:

0.00612

GnomAD3 exomes

AF:

0.00106

AC:

256

AN:

240710

Hom.:

AF XY:

0.000995

AC XY:

130

AN XY:

130690

show subpopulations

Gnomad AFR exome

AF:

0.000451

Gnomad AMR exome

AF:

0.000921

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000142

Gnomad NFE exome

AF:

0.00189

Gnomad OTH exome

AF:

0.00189

GnomAD4 exome

AF:

0.00215

AC:

3102

AN:

1443796

Hom.:

Cov.:

AF XY:

0.00210

AC XY:

1510

AN XY:

718284

show subpopulations

Gnomad4 AFR exome

AF:

0.000399

Gnomad4 AMR exome

AF:

0.00123

Gnomad4 ASJ exome

AF:

0.0000391

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000248

Gnomad4 NFE exome

AF:

0.00264

Gnomad4 OTH exome

AF:

0.00190

GnomAD4 genome

AF:

0.00221

AC:

236

AN:

106804

Hom.:

Cov.:

AF XY:

0.00205

AC XY:

103

AN XY:

50338

show subpopulations

Gnomad4 AFR

AF:

0.000533

Gnomad4 AMR

AF:

0.00784

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000196

Gnomad4 NFE

AF:

0.00256

Gnomad4 OTH

AF:

0.00606

Alfa

AF:

0.00118

Hom.:

Bravo

AF:

0.00218

ESP6500AA

AF:

0.00113

AC:

ESP6500EA

AF:

0.00291

AC:

ExAC

AF:

0.00106

AC:

129

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Amelogenesis imperfecta hypomaturation type 2A2

Pathogenic:4

Pathogenic, criteria provided, single submitter	research	HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	Nov 09, 2022	ACMG codes:PVS1_VeryStrong, PM2_Supporting, PM3_Strong -
Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 01, 2005	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Sep 20, 2024	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with amelogenesis imperfecta, type IIA2 (MIM#612529). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0211 - Canonical splice site variant without proven consequence on splicing (no functional evidence available). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v3) <0.01 for a recessive condition (234 heterozygotes, 1 homozygote). (SP) 0505 - Abnormal splicing is predicted by in silico tools and affected nucleotide is highly conserved. (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic by multiple clinical laboratories in ClinVar, and as a VUS in one older entry. This variant has also been observed in homozygous and compound heterozygous individuals with amelogenesis imperfecta, including individuals compound heterozygous with c.103A>C (PMID: 15744043, 33600052, 37228816, 26502894). (SP) 1201- Heterozygous variant detected in trans with a second pathogenic heterozygous variant, NM_004771.3(MMP20):c.103A>C p.(Arg35=), in a recessive disease. (I) 1205 - This variant has been shown to be maternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Sep 05, 2024	- -

not provided

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 15, 2022	Canonical splice site variant in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 31980526, 25525159, 15744043, 22243262, 28659819, 26502894, 21597265, 16246936, 26124219, 16838342, 32495503, 31589614, 33600052) -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	May 13, 2019	This sequence change affects an acceptor splice site in intron 6 of the MMP20 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is present in population databases (rs140213840, ExAC 0.2%). This variant has been reported in several families and individuals affected with autosomal recessive pigmented hypomaturation amelogenesis imperfecta (PMID: 15744043, 22243262, 21597265, 26502894). ClinVar contains an entry for this variant (Variation ID: 5428). Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in MMP20 are known to be pathogenic (PMID: 18096894, 23625376). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2023	MMP20: PVS1, PM3, PM2:Supporting -

MMP20-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 03, 2024

The MMP20 c.954-2A>T variant is predicted to disrupt the AG splice acceptor site and interfere with normal splicing. This variant has been previously reported in the homozygous or compound heterozygous state in several individuals with autosomal recessive amelogenesis imperfecta (Kim et al. 2005. PubMed ID: 15744043; Chan et al. 2011. PubMed ID: 22243262; Wright et al. 2011. PubMed ID: 21597265; Gasse et al. 2013. PubMed ID: 23625376; Prasad et al. 2016. PubMed ID: 26502894; Wang et al. 2020. PubMed ID: 32495503). It has also been identified in a genome sequencing cohort and interpreted as likely pathogenic (Hou et al. 2020. PubMed ID: 31980526). This variant is reported in 0.19% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Variants that disrupt the consensus splice acceptor site in MMP20 are expected to be pathogenic. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.31

BayesDel_noAF

Pathogenic

0.23

CADD

Pathogenic

DANN

Uncertain

0.99

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.84

FATHMM_MKL

Pathogenic

0.98

GERP RS

5.4

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.94

SpliceAI score (max)

0.99

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.52

Position offset: -14

DS_AL_spliceai

0.99

Position offset: -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