11-102609091-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_004771.4(MMP20):​c.657T>A​(p.Asn219Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Consequence

MMP20
NM_004771.4 missense

Scores

4
8
7

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.0950
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.929

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
MMP20NM_004771.4 linkuse as main transcriptc.657T>A p.Asn219Lys missense_variant 5/10 ENST00000260228.3 NP_004762.2 O60882

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
MMP20ENST00000260228.3 linkuse as main transcriptc.657T>A p.Asn219Lys missense_variant 5/101 NM_004771.4 ENSP00000260228.2 O60882
MMP20-AS1ENST00000542119.1 linkuse as main transcriptn.86+1639A>T intron_variant 3

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
32
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsDec 01, 2023The c.657T>A (p.N219K) alteration is located in exon 5 (coding exon 5) of the MMP20 gene. This alteration results from a T to A substitution at nucleotide position 657, causing the asparagine (N) at amino acid position 219 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.98
BayesDel_addAF
Benign
-0.040
T
BayesDel_noAF
Benign
-0.29
CADD
Benign
21
DANN
Uncertain
1.0
DEOGEN2
Benign
0.24
T
Eigen
Uncertain
0.47
Eigen_PC
Uncertain
0.34
FATHMM_MKL
Uncertain
0.89
D
LIST_S2
Benign
0.80
T
M_CAP
Benign
0.028
D
MetaRNN
Pathogenic
0.93
D
MetaSVM
Benign
-0.84
T
MutationAssessor
Pathogenic
3.4
M
PrimateAI
Uncertain
0.66
T
PROVEAN
Pathogenic
-5.6
D
REVEL
Uncertain
0.42
Sift
Uncertain
0.0010
D
Sift4G
Uncertain
0.0020
D
Polyphen
1.0
D
Vest4
0.81
MutPred
0.85
Gain of methylation at N219 (P = 0.0071);
MVP
0.68
MPC
0.28
ClinPred
0.99
D
GERP RS
3.0
Varity_R
0.98
gMVP
0.78

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-102479822; API