chr20-46008928-T-A
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PVS1_SupportingBS2
The NM_004994.3(MMP9):c.2T>A(p.Met1?) variant causes a start lost change. The variant allele was found at a frequency of 0.000385 in 1,612,276 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Consequence
NM_004994.3 start_lost
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -3 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000276 AC: 42AN: 152130Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.000745 AC: 187AN: 250880Hom.: 2 AF XY: 0.00106 AC XY: 144AN XY: 135668
GnomAD4 exome AF: 0.000396 AC: 578AN: 1460028Hom.: 5 Cov.: 33 AF XY: 0.000556 AC XY: 404AN XY: 726394
GnomAD4 genome AF: 0.000276 AC: 42AN: 152248Hom.: 0 Cov.: 31 AF XY: 0.000336 AC XY: 25AN XY: 74458
ClinVar
Submissions by phenotype
Metaphyseal anadysplasia 2 Pathogenic:1Uncertain:2
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
NM_004994.2:c.2T>A in the MMP9 gene has an allele frequency of 0.006 in South Asian subpopulation in the gnomAD database. This variant occurs in the initiation codon and is predicted to affect protein translation. The closest potential in-frame start codon was observed at amino acid 60. From the original star codon to amino acid 60, there is one P/LP variant reported in ClinVar. In addition, this variant has been detected in an individual with Metaphyseal Anadysplasia (PMID: 19615667). Taken together, we interprete this variant as variant of uncertain significance (VUS). ACMG/AMP Criteria applied: PVS1_Moderate; PM2; PP4. -
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not provided Uncertain:1
This sequence change affects the initiator methionine of the MMP9 mRNA. The next in-frame methionine is located at codon 60. This variant is present in population databases (rs121434556, gnomAD 0.6%), and has an allele count higher than expected for a pathogenic variant. Disruption of the initiator codon has been observed in individual(s) with metaphyseal anadysplasia (PMID: 19615667). ClinVar contains an entry for this variant (Variation ID: 17107). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at