11-102840251-T-C

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_002422.5(MMP3):c.792A>G(p.Gly264=) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00384 in 1,611,888 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0028 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0039 (15 hom.)
• Consequence: MMP3 NM_002422.5 splice_region, synonymous
• Scores: Splicing: ADA: 0.00001942
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.160

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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 11-102840251-T-C is Benign according to our data. Variant chr11-102840251-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 770980.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.16 with no splicing effect.
• BS2: High AC in GnomAd at 421 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MMP3	NM_002422.5	c.792A>G	p.Gly264=	splice_region_variant, synonymous_variant	6/10	ENST00000299855.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MMP3	ENST00000299855.10	c.792A>G	p.Gly264=	splice_region_variant, synonymous_variant	6/10	1	NM_002422.5	P1

Frequencies

GnomAD3 genomes AF: 0.00277 AC: 421 AN: 151818 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000921

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00461

Gnomad ASJ AF: 0.00520

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000625

Gnomad FIN AF: 0.000851

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00397

Gnomad OTH AF: 0.00621

GnomAD3 exomes AF: 0.00278 AC: 691 AN: 248584 Hom.: 2 AF XY: 0.00272 AC XY: 366 AN XY: 134384

Gnomad AFR exome AF: 0.000805

Gnomad AMR exome AF: 0.00488

Gnomad ASJ exome AF: 0.00518

Gnomad EAS exome AF: 0.0000548

Gnomad SAS exome AF: 0.00106

Gnomad FIN exome AF: 0.000744

Gnomad NFE exome AF: 0.00351

Gnomad OTH exome AF: 0.00281

GnomAD4 exome AF: 0.00395 AC: 5766 AN: 1459952 Hom.: 15 Cov.: 31 AF XY: 0.00388 AC XY: 2819 AN XY: 726258

Gnomad4 AFR exome AF: 0.000749

Gnomad4 AMR exome AF: 0.00520

Gnomad4 ASJ exome AF: 0.00498

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00118

Gnomad4 FIN exome AF: 0.000899

Gnomad4 NFE exome AF: 0.00450

Gnomad4 OTH exome AF: 0.00377

GnomAD4 genome AF: 0.00277 AC: 421 AN: 151936 Hom.: 1 Cov.: 32 AF XY: 0.00257 AC XY: 191 AN XY: 74256

Gnomad4 AFR AF: 0.000918

Gnomad4 AMR AF: 0.00460

Gnomad4 ASJ AF: 0.00520

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000625

Gnomad4 FIN AF: 0.000851

Gnomad4 NFE AF: 0.00397

Gnomad4 OTH AF: 0.00614

Alfa AF: 0.00386 Hom.: 3

Bravo AF: 0.00316

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

- -

MMP3-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 07, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
Cadd	Benign	6.6
Dann	Benign	0.61

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000019
dbscSNV1_RF	Benign	0.010
SpliceAI score (max)		0.010		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: rs3025065; hg19: chr11-102710982;