rs140213840

Variant names:

• chr11-102594759-T-A
• rs140213840
• NM_004771.4:c.954-2A>T

Your query was ambiguous. Multiple possible variants found:

• chr11-102594759-T-A
• chr11-102594759-T-C

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 16P and 1B. PVS1 PP5_Very_Strong BS1_Supporting

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

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 Pathogenic. Variant got 15 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].
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00221 (236/106804) while in subpopulation AMR AF= 0.00784 (74/9434). AF 95% confidence interval is 0.00641. There are 1 homozygotes in gnomad4. There are 103 alleles in male gnomad4 subpopulation. Median coverage is 26. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MMP20	NM_004771.4	c.954-2A>T		splice_acceptor_variant, intron_variant	Intron 6 of 9	ENST00000260228.3	NP_004762.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MMP20	ENST00000260228.3	c.954-2A>T		splice_acceptor_variant, intron_variant	Intron 6 of 9	1	NM_004771.4	ENSP00000260228.2
MMP20	ENST00000544938.1	n.593-2A>T		splice_acceptor_variant, intron_variant	Intron 4 of 4	3

Frequencies

GnomAD3 genomes AF: 0.00221 AC: 236 AN: 106738 Hom.: 1 Cov.: 26

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.: 0 AF XY: 0.000995 AC XY: 130 AN XY: 130690

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.: 4 Cov.: 36 AF XY: 0.00210 AC XY: 1510 AN XY: 718284

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.: 1 Cov.: 26 AF XY: 0.00205 AC XY: 103 AN XY: 50338

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.: 0

Bravo AF: 0.00218

ESP6500AA AF: 0.00113 AC: 5

ESP6500EA AF: 0.00291 AC: 25

ExAC AF: 0.00106 AC: 129

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Amelogenesis imperfecta hypomaturation type 2A2 Pathogenic:4

Nov 09, 2022

HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

ACMG codes:PVS1_VeryStrong, PM2_Supporting, PM3_Strong -

Mar 01, 2005

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Sep 20, 2024

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 -

Oct 23, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

not provided Pathogenic:3

Sep 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

MMP20: PVS1, PM3, PM2:Supporting -

Jun 15, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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) -

May 13, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

MMP20-related disorder Pathogenic:1

Sep 03, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

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	D
BayesDel_noAF	Pathogenic	0.23
CADD	Pathogenic	32
DANN	Uncertain	0.99
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Pathogenic	0.98	D
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

Other links and lift over

dbSNP: rs140213840; hg19: chr11-102465490;