11-102577099-T-G

Variant names:

• chr11-102577099-T-G
• rs12278482
• NM_004771.4:c.*227A>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004771.4(MMP20):​c.*227A>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00616 in 513,402 control chromosomes in the GnomAD database, including 82 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.016 (66 hom., cov: 33)
  • Exomes 𝑓: 0.0018 (16 hom.)
• Consequence: MMP20 NM_004771.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 3.08
• Publications: 2 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 11-102577099-T-G is Benign according to our data. Variant chr11-102577099-T-G is described in ClinVar as [Benign]. Clinvar id is 880332.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.054 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MMP20	NM_004771.4	c.*227A>C		3_prime_UTR_variant	Exon 10 of 10	ENST00000260228.3	NP_004762.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MMP20	ENST00000260228.3	c.*227A>C		3_prime_UTR_variant	Exon 10 of 10	1	NM_004771.4	ENSP00000260228.2
MMP20	ENST00000542305.1	n.*45A>C		downstream_gene_variant		2

Frequencies

GnomAD3 genomes AF: 0.0163 AC: 2484 AN: 152206 Hom.: 65 Cov.: 33

Gnomad AFR AF: 0.0558

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00910

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.0124

GnomAD4 exome AF: 0.00185 AC: 667 AN: 361078 Hom.: 16 Cov.: 0 AF XY: 0.00152 AC XY: 294 AN XY: 193902

African (AFR) AF: 0.0541 AC: 556 AN: 10274

American (AMR) AF: 0.00270 AC: 43 AN: 15952

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 10540

East Asian (EAS) AF: 0.00 AC: 0 AN: 22470

South Asian (SAS) AF: 0.0000230 AC: 1 AN: 43394

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 20158

Middle Eastern (MID) AF: 0.00131 AC: 2 AN: 1530

European-Non Finnish (NFE) AF: 0.0000416 AC: 9 AN: 216310

Other (OTH) AF: 0.00274 AC: 56 AN: 20450

GnomAD4 genome AF: 0.0164 AC: 2496 AN: 152324 Hom.: 66 Cov.: 33 AF XY: 0.0156 AC XY: 1160 AN XY: 74494

African (AFR) AF: 0.0559 AC: 2325 AN: 41570

American (AMR) AF: 0.00909 AC: 139 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000882 AC: 6 AN: 68042

Other (OTH) AF: 0.0123 AC: 26 AN: 2112

Alfa AF: 0.00600 Hom.: 28

Bravo AF: 0.0193

Asia WGS AF: 0.00318 AC: 11 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Jun 20, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Amelogenesis imperfecta hypomaturation type 2A2 Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	6.6
DANN	Benign	0.49
PhyloP100		3.1
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs12278482; hg19: chr11-102447830;