20-46016371-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004994.3(MMP9):c.*3C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.516 in 1,611,636 control chromosomes in the GnomAD database, including 230,116 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.43 (16128 hom., cov: 31)
  • Exomes 𝑓: 0.52 (213988 hom.)
• Consequence: MMP9 NM_004994.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.65

Genes affected

MMP9 (HGNC:7176): (matrix metallopeptidase 9) 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 enzyme encoded by this gene degrades type IV and V collagens. Studies in rhesus monkeys suggest that the enzyme is involved in IL-8-induced mobilization of hematopoietic progenitor cells from bone marrow, and murine studies suggest a role in tumor-associated tissue remodeling. [provided by RefSeq, Jul 2008]

SLC12A5-AS1 (HGNC:53143): (SLC12A5 and MMP9 antisense RNA 1)

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.69).
• BP6: Variant 20-46016371-C-T is Benign according to our data. Variant chr20-46016371-C-T is described in ClinVar as [Benign]. Clinvar id is 338562.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-46016371-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.571 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MMP9	NM_004994.3	c.*3C>T		3_prime_UTR_variant	13/13	ENST00000372330.3
SLC12A5-AS1	NR_147699.1	n.669-1583G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MMP9	ENST00000372330.3	c.*3C>T		3_prime_UTR_variant	13/13	1	NM_004994.3	P1
SLC12A5-AS1	ENST00000535913.2	n.669-1583G>A		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.431 AC: 65522 AN: 151880 Hom.: 16133 Cov.: 31

Gnomad AFR AF: 0.253

Gnomad AMI AF: 0.568

Gnomad AMR AF: 0.388

Gnomad ASJ AF: 0.505

Gnomad EAS AF: 0.00424

Gnomad SAS AF: 0.306

Gnomad FIN AF: 0.480

Gnomad MID AF: 0.579

Gnomad NFE AF: 0.576

Gnomad OTH AF: 0.473

GnomAD3 exomes AF: 0.426 AC: 107143 AN: 251334 Hom.: 27095 AF XY: 0.436 AC XY: 59280 AN XY: 135848

Gnomad AFR exome AF: 0.249

Gnomad AMR exome AF: 0.258

Gnomad ASJ exome AF: 0.507

Gnomad EAS exome AF: 0.00228

Gnomad SAS exome AF: 0.322

Gnomad FIN exome AF: 0.481

Gnomad NFE exome AF: 0.579

Gnomad OTH exome AF: 0.487

GnomAD4 exome AF: 0.525 AC: 766129 AN: 1459638 Hom.: 213988 Cov.: 32 AF XY: 0.521 AC XY: 378490 AN XY: 726260

Gnomad4 AFR exome AF: 0.237

Gnomad4 AMR exome AF: 0.270

Gnomad4 ASJ exome AF: 0.501

Gnomad4 EAS exome AF: 0.00139

Gnomad4 SAS exome AF: 0.327

Gnomad4 FIN exome AF: 0.494

Gnomad4 NFE exome AF: 0.581

Gnomad4 OTH exome AF: 0.497

GnomAD4 genome AF: 0.431 AC: 65521 AN: 151998 Hom.: 16128 Cov.: 31 AF XY: 0.420 AC XY: 31243 AN XY: 74322

Gnomad4 AFR AF: 0.253

Gnomad4 AMR AF: 0.388

Gnomad4 ASJ AF: 0.505

Gnomad4 EAS AF: 0.00406

Gnomad4 SAS AF: 0.307

Gnomad4 FIN AF: 0.480

Gnomad4 NFE AF: 0.576

Gnomad4 OTH AF: 0.468

Alfa AF: 0.536 Hom.: 27780

Bravo AF: 0.413

Asia WGS AF: 0.158 AC: 556 AN: 3478

EpiCase AF: 0.580

EpiControl AF: 0.582

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Metaphyseal anadysplasia 2 Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 12, 2018	This variant is associated with the following publications: (PMID: 28623238) -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 22, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
Cadd	Benign	13
Dann	Benign	0.75

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

LitVar

Other links and lift over

dbSNP: rs20544; hg19: chr20-44645010; COSMIC: COSV63434141; COSMIC: COSV63434141;