11-102594759-T-A

Variant names:

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

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 16P and 5B. PVS1 PP5_Very_Strong BS1_Supporting BS2

The ENST00000260228.3(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 ENST00000260228.3 splice_acceptor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:9
• Conservation: PhyloP100: 4.96
• Publications: 12 publications found

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 Gene-Disease associations (from GenCC):

• amelogenesis imperfecta hypomaturation type 2A2

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• amelogenesis imperfecta type 2

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 11 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 VariationId is 5428.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 the male GnomAd4 subpopulation. Median coverage is 26. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAdExome4 at 4 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000260228.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MMP20	NM_004771.4	MANE Select	c.954-2A>T		splice_acceptor intron	N/A	NP_004762.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MMP20	ENST00000260228.3	TSL:1 MANE Select	c.954-2A>T		splice_acceptor intron	N/A	ENSP00000260228.2
	MMP20	ENST00000544938.1	TSL:3	n.593-2A>T		splice_acceptor intron	N/A

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

GnomAD2 exomes AF: 0.00106 AC: 256 AN: 240710 AF XY: 0.000995

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 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

African (AFR) AF: 0.000399 AC: 13 AN: 32612

American (AMR) AF: 0.00123 AC: 53 AN: 42942

Ashkenazi Jewish (ASJ) AF: 0.0000391 AC: 1 AN: 25574

East Asian (EAS) AF: 0.00 AC: 0 AN: 39304

South Asian (SAS) AF: 0.00 AC: 0 AN: 84090

European-Finnish (FIN) AF: 0.000248 AC: 13 AN: 52466

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4678

European-Non Finnish (NFE) AF: 0.00264 AC: 2909 AN: 1102700

Other (OTH) AF: 0.00190 AC: 113 AN: 59430

GnomAD4 genome AF: 0.00221 AC: 236 AN: 106804 Hom.: 1 Cov.: 26 AF XY: 0.00205 AC XY: 103 AN XY: 50338

African (AFR) AF: 0.000533 AC: 14 AN: 26250

American (AMR) AF: 0.00784 AC: 74 AN: 9434

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2876

East Asian (EAS) AF: 0.00 AC: 0 AN: 3636

South Asian (SAS) AF: 0.00 AC: 0 AN: 2880

European-Finnish (FIN) AF: 0.000196 AC: 1 AN: 5108

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 208

European-Non Finnish (NFE) AF: 0.00256 AC: 139 AN: 54350

Other (OTH) AF: 0.00606 AC: 8 AN: 1320

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

ClinVar submissions as Germline

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
4	-	-	Amelogenesis imperfecta hypomaturation type 2A2 (4)
3	-	-	not provided (3)
1	-	-	Inborn genetic diseases (1)
1	-	-	MMP20-related disorder (1)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		5.0
GERP RS		5.4
Mutation Taster		=4/96	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs140213840; hg19: chr11-102465490;