rs13969

chr20-46014194-A-Cchr20-46014194-A-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_004994.3(MMP9):c.1821A>C(p.Gly607=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.572 in 1,537,284 control chromosomes in the GnomAD database, including 257,695 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.53 (21915 hom., cov: 33)
  • Exomes 𝑓: 0.58 (235780 hom.)
• Consequence: MMP9 NM_004994.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -2.24

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).
• BP6: Variant 20-46014194-A-C is Benign according to our data. Variant chr20-46014194-A-C is described in ClinVar as [Benign]. Clinvar id is 285363.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-46014194-A-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-2.24 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.603 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MMP9	NM_004994.3	c.1821A>C	p.Gly607=	synonymous_variant	11/13	ENST00000372330.3
SLC12A5-AS1	NR_147699.1	n.1263T>G		non_coding_transcript_exon_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MMP9	ENST00000372330.3	c.1821A>C	p.Gly607=	synonymous_variant	11/13	1	NM_004994.3	P1
SLC12A5-AS1	ENST00000535913.2	n.1263T>G		non_coding_transcript_exon_variant	3/3	2

Frequencies

GnomAD3 genomes AF: 0.528 AC: 80229 AN: 151966 Hom.: 21914 Cov.: 33

Gnomad AFR AF: 0.433

Gnomad AMI AF: 0.651

Gnomad AMR AF: 0.542

Gnomad ASJ AF: 0.573

Gnomad EAS AF: 0.239

Gnomad SAS AF: 0.385

Gnomad FIN AF: 0.540

Gnomad MID AF: 0.598

Gnomad NFE AF: 0.607

Gnomad OTH AF: 0.555

GnomAD3 exomes AF: 0.499 AC: 67779 AN: 135832 Hom.: 17974 AF XY: 0.497 AC XY: 36750 AN XY: 73898

Gnomad AFR exome AF: 0.415

Gnomad AMR exome AF: 0.457

Gnomad ASJ exome AF: 0.565

Gnomad EAS exome AF: 0.246

Gnomad SAS exome AF: 0.402

Gnomad FIN exome AF: 0.533

Gnomad NFE exome AF: 0.606

Gnomad OTH exome AF: 0.543

GnomAD4 exome AF: 0.577 AC: 799523 AN: 1385202 Hom.: 235780 Cov.: 63 AF XY: 0.573 AC XY: 391217 AN XY: 683186

Gnomad4 AFR exome AF: 0.423

Gnomad4 AMR exome AF: 0.466

Gnomad4 ASJ exome AF: 0.566

Gnomad4 EAS exome AF: 0.239

Gnomad4 SAS exome AF: 0.403

Gnomad4 FIN exome AF: 0.547

Gnomad4 NFE exome AF: 0.611

Gnomad4 OTH exome AF: 0.561

GnomAD4 genome AF: 0.528 AC: 80263 AN: 152082 Hom.: 21915 Cov.: 33 AF XY: 0.521 AC XY: 38745 AN XY: 74348

Gnomad4 AFR AF: 0.433

Gnomad4 AMR AF: 0.542

Gnomad4 ASJ AF: 0.573

Gnomad4 EAS AF: 0.238

Gnomad4 SAS AF: 0.387

Gnomad4 FIN AF: 0.540

Gnomad4 NFE AF: 0.607

Gnomad4 OTH AF: 0.549

Alfa AF: 0.530 Hom.: 4186

Bravo AF: 0.520

Asia WGS AF: 0.317 AC: 1107 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

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	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Jun 28, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
Cadd	Benign	12
Dann	Benign	0.74

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: rs13969; hg19: chr20-44642833; COSMIC: COSV63433888;