rs2236304

Positions:

• chr14-22843654-C-G

Variant summary

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

The NM_004995.4(MMP14):​c.851-56C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.318 in 1,541,604 control chromosomes in the GnomAD database, including 81,272 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.28 (6931 hom., cov: 31)
  • Exomes 𝑓: 0.32 (74341 hom.)
• Consequence: MMP14 NM_004995.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.278

Genes affected

MMP14 (HGNC:7160): (matrix metallopeptidase 14) 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. However, the protein encoded by this gene is a member of the membrane-type MMP (MT-MMP) subfamily; each member of this subfamily contains a potential transmembrane domain suggesting that these proteins are expressed at the cell surface rather than secreted. This protein activates MMP2 protein, and this activity may be involved in tumor invasion. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 14-22843654-C-G is Benign according to our data. Variant chr14-22843654-C-G is described in ClinVar as [Benign]. Clinvar id is 1272389.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.451 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MMP14	NM_004995.4	c.851-56C>G		intron_variant		ENST00000311852.11	NP_004986.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MMP14	ENST00000311852.11	c.851-56C>G		intron_variant		1	NM_004995.4	ENSP00000308208.6
MMP14	ENST00000548162.2	c.851-56C>G		intron_variant		5		ENSP00000506068.1
MMP14	ENST00000680097.1	n.*166-56C>G		intron_variant				ENSP00000506631.1
MMP14	ENST00000680941.1	n.*249-56C>G		intron_variant				ENSP00000506378.1

Frequencies

GnomAD3 genomes AF: 0.282 AC: 42813 AN: 151826 Hom.: 6929 Cov.: 31

Gnomad AFR AF: 0.122

Gnomad AMI AF: 0.148

Gnomad AMR AF: 0.377

Gnomad ASJ AF: 0.366

Gnomad EAS AF: 0.467

Gnomad SAS AF: 0.258

Gnomad FIN AF: 0.393

Gnomad MID AF: 0.278

Gnomad NFE AF: 0.326

Gnomad OTH AF: 0.283

GnomAD4 exome AF: 0.322 AC: 447690 AN: 1389660 Hom.: 74341 Cov.: 28 AF XY: 0.320 AC XY: 219643 AN XY: 686788

Gnomad4 AFR exome AF: 0.114

Gnomad4 AMR exome AF: 0.465

Gnomad4 ASJ exome AF: 0.383

Gnomad4 EAS exome AF: 0.474

Gnomad4 SAS exome AF: 0.251

Gnomad4 FIN exome AF: 0.383

Gnomad4 NFE exome AF: 0.319

Gnomad4 OTH exome AF: 0.320

GnomAD4 genome AF: 0.282 AC: 42819 AN: 151944 Hom.: 6931 Cov.: 31 AF XY: 0.287 AC XY: 21326 AN XY: 74228

Gnomad4 AFR AF: 0.122

Gnomad4 AMR AF: 0.377

Gnomad4 ASJ AF: 0.366

Gnomad4 EAS AF: 0.467

Gnomad4 SAS AF: 0.259

Gnomad4 FIN AF: 0.393

Gnomad4 NFE AF: 0.326

Gnomad4 OTH AF: 0.281

Alfa AF: 0.299 Hom.: 901

Bravo AF: 0.278

Asia WGS AF: 0.338 AC: 1175 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 14, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	4.9
DANN	Benign	0.65

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: rs2236304; hg19: chr14-23312863; COSMIC: COSV61287316; COSMIC: COSV61287316;