chr11-102608925-TAATAATCTTACCGT-CTGG

Position:

• chr11-102608925-TAATAATCTTACCGT-CTGG

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PVS1_Strong PM2 PP5

The NM_004771.4(MMP20):​c.809_811+12delinsCCAG variant causes a splice donor, splice donor 5th base, coding sequence, intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars). Synonymous variant affecting the same amino acid position (i.e. Y270Y) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MMP20 NM_004771.4 splice_donor, splice_donor_5th_base, coding_sequence, intron
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 1.24

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-AS1 (HGNC:56362): (MMP20 antisense RNA 1)

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.110881545 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-102608925-TAATAATCTTACCGT-CTGG is Pathogenic according to our data. Variant chr11-102608925-TAATAATCTTACCGT-CTGG is described in ClinVar as [Pathogenic]. Clinvar id is 917993.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MMP20	NM_004771.4	c.809_811+12delinsCCAG		splice_donor_variant, splice_donor_5th_base_variant, coding_sequence_variant, intron_variant	5/10	ENST00000260228.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MMP20	ENST00000260228.3	c.809_811+12delinsCCAG		splice_donor_variant, splice_donor_5th_base_variant, coding_sequence_variant, intron_variant	5/10	1	NM_004771.4	P1
MMP20-AS1	ENST00000542119.1	n.86+1473_86+1487delinsCTGG		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Amelogenesis imperfecta hypomaturation type 2A2 Pathogenic:1

Pathogenic, no assertion criteria provided

research

Leeds Amelogenesis Imperfecta Research Group, University of Leeds

Jun 11, 2020

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Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1859555583; hg19: chr11-102479656;