11-102842889-T-C

Variant names:

• chr11-102842889-T-C
• rs679620
• NM_002422.5:c.133A>G

Variant summary

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

The NM_002422.5(MMP3):​c.133A>G​(p.Lys45Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.526 in 1,608,044 control chromosomes in the GnomAD database, including 227,326 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

• Frequency:
  • Genomes: 𝑓 0.58 (25701 hom., cov: 31)
  • Exomes 𝑓: 0.52 (201625 hom.)
• Consequence: MMP3 NM_002422.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.176

Genes affected

MMP3 (HGNC:7173): (matrix metallopeptidase 3) 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. This gene encodes an enzyme which degrades fibronectin, laminin, collagens III, IV, IX, and X, and cartilage proteoglycans. The enzyme is thought to be involved in wound repair, progression of atherosclerosis, and tumor initiation. The gene is part of a cluster of MMP genes which localize to chromosome 11q22.3. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.954977E-6).
• BP6: Variant 11-102842889-T-C is Benign according to our data. Variant chr11-102842889-T-C is described in ClinVar as [Benign]. Clinvar id is 403098.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.677 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MMP3	NM_002422.5	c.133A>G	p.Lys45Glu	missense_variant	Exon 2 of 10	ENST00000299855.10	NP_002413.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MMP3	ENST00000299855.10	c.133A>G	p.Lys45Glu	missense_variant	Exon 2 of 10	1	NM_002422.5	ENSP00000299855.5
MMP3	ENST00000524478.1	n.104A>G		non_coding_transcript_exon_variant	Exon 2 of 4	4		ENSP00000435255.1

Frequencies

GnomAD3 genomes AF: 0.575 AC: 87307 AN: 151766 Hom.: 25663 Cov.: 31

Gnomad AFR AF: 0.653

Gnomad AMI AF: 0.582

Gnomad AMR AF: 0.638

Gnomad ASJ AF: 0.614

Gnomad EAS AF: 0.673

Gnomad SAS AF: 0.697

Gnomad FIN AF: 0.605

Gnomad MID AF: 0.566

Gnomad NFE AF: 0.491

Gnomad OTH AF: 0.559

GnomAD3 exomes AF: 0.580 AC: 142818 AN: 246160 Hom.: 42358 AF XY: 0.576 AC XY: 76667 AN XY: 133034

Gnomad AFR exome AF: 0.653

Gnomad AMR exome AF: 0.703

Gnomad ASJ exome AF: 0.606

Gnomad EAS exome AF: 0.666

Gnomad SAS exome AF: 0.674

Gnomad FIN exome AF: 0.589

Gnomad NFE exome AF: 0.490

Gnomad OTH exome AF: 0.551

GnomAD4 exome AF: 0.521 AC: 758719 AN: 1456160 Hom.: 201625 Cov.: 37 AF XY: 0.526 AC XY: 380836 AN XY: 724274

Gnomad4 AFR exome AF: 0.659

Gnomad4 AMR exome AF: 0.695

Gnomad4 ASJ exome AF: 0.609

Gnomad4 EAS exome AF: 0.679

Gnomad4 SAS exome AF: 0.674

Gnomad4 FIN exome AF: 0.584

Gnomad4 NFE exome AF: 0.486

Gnomad4 OTH exome AF: 0.544

GnomAD4 genome AF: 0.575 AC: 87403 AN: 151884 Hom.: 25701 Cov.: 31 AF XY: 0.584 AC XY: 43358 AN XY: 74232

Gnomad4 AFR AF: 0.654

Gnomad4 AMR AF: 0.639

Gnomad4 ASJ AF: 0.614

Gnomad4 EAS AF: 0.673

Gnomad4 SAS AF: 0.697

Gnomad4 FIN AF: 0.605

Gnomad4 NFE AF: 0.492

Gnomad4 OTH AF: 0.560

Alfa AF: 0.518 Hom.: 24878

Bravo AF: 0.581

TwinsUK AF: 0.482 AC: 1787

ALSPAC AF: 0.494 AC: 1904

ESP6500AA AF: 0.639 AC: 2815

ESP6500EA AF: 0.500 AC: 4301

ExAC AF: 0.570 AC: 69190

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nov 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 26771213, 19008710, 19406964, 25525159, 19551141, 21753786) -

not specified Benign:1

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.84	T
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.22
DANN	Benign	0.28
DEOGEN2	Benign	0.11	T
Eigen	Benign	-1.9
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.035	N
LIST_S2	Benign	0.0030	T
MetaRNN	Benign	0.0000020	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	-0.090	N
PrimateAI	Benign	0.30	T
PROVEAN	Benign	0.020	N
REVEL	Benign	0.0070
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.036
MPC		0.017
ClinPred		0.00055	T
GERP RS		-0.22
Varity_R		0.12
gMVP		0.49

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs679620; hg19: chr11-102713620; COSMIC: COSV55405241; COSMIC: COSV55405241;