chr14-22843345-C-G

Position:

• chr14-22843345-C-G

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The ENST00000311852.11(MMP14):​c.777C>G​(p.Pro259=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.114 in 1,613,690 control chromosomes in the GnomAD database, including 11,861 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. P259P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.16 (2360 hom., cov: 31)
  • Exomes 𝑓: 0.11 (9501 hom.)
• Consequence: MMP14 ENST00000311852.11 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.469

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.41).
• BP6: Variant 14-22843345-C-G is Benign according to our data. Variant chr14-22843345-C-G is described in ClinVar as [Benign]. Clinvar id is 1232955.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.469 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.281 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MMP14	NM_004995.4	c.777C>G	p.Pro259=	synonymous_variant	5/10	ENST00000311852.11	NP_004986.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MMP14	ENST00000311852.11	c.777C>G	p.Pro259=	synonymous_variant	5/10	1	NM_004995.4	ENSP00000308208	P1
MMP14	ENST00000548162.2	c.777C>G	p.Pro259=	synonymous_variant	5/10	5		ENSP00000506068
MMP14	ENST00000680097.1	c.*92C>G		3_prime_UTR_variant, NMD_transcript_variant	5/10			ENSP00000506631
MMP14	ENST00000680941.1	c.*175C>G		3_prime_UTR_variant, NMD_transcript_variant	6/11			ENSP00000506378

Frequencies

GnomAD3 genomes AF: 0.158 AC: 23971 AN: 151940 Hom.: 2355 Cov.: 31

Gnomad AFR AF: 0.285

Gnomad AMI AF: 0.0362

Gnomad AMR AF: 0.139

Gnomad ASJ AF: 0.109

Gnomad EAS AF: 0.128

Gnomad SAS AF: 0.0692

Gnomad FIN AF: 0.105

Gnomad MID AF: 0.130

Gnomad NFE AF: 0.105

Gnomad OTH AF: 0.167

GnomAD3 exomes AF: 0.123 AC: 30878 AN: 251318 Hom.: 2269 AF XY: 0.116 AC XY: 15766 AN XY: 135842

Gnomad AFR exome AF: 0.295

Gnomad AMR exome AF: 0.153

Gnomad ASJ exome AF: 0.100

Gnomad EAS exome AF: 0.133

Gnomad SAS exome AF: 0.0671

Gnomad FIN exome AF: 0.112

Gnomad NFE exome AF: 0.107

Gnomad OTH exome AF: 0.117

GnomAD4 exome AF: 0.109 AC: 159160 AN: 1461632 Hom.: 9501 Cov.: 32 AF XY: 0.107 AC XY: 77940 AN XY: 727110

Gnomad4 AFR exome AF: 0.294

Gnomad4 AMR exome AF: 0.150

Gnomad4 ASJ exome AF: 0.103

Gnomad4 EAS exome AF: 0.120

Gnomad4 SAS exome AF: 0.0667

Gnomad4 FIN exome AF: 0.107

Gnomad4 NFE exome AF: 0.104

Gnomad4 OTH exome AF: 0.116

GnomAD4 genome AF: 0.158 AC: 23998 AN: 152058 Hom.: 2360 Cov.: 31 AF XY: 0.156 AC XY: 11579 AN XY: 74334

Gnomad4 AFR AF: 0.285

Gnomad4 AMR AF: 0.139

Gnomad4 ASJ AF: 0.109

Gnomad4 EAS AF: 0.128

Gnomad4 SAS AF: 0.0686

Gnomad4 FIN AF: 0.105

Gnomad4 NFE AF: 0.105

Gnomad4 OTH AF: 0.165

Alfa AF: 0.0898 Hom.: 275

Bravo AF: 0.170

Asia WGS AF: 0.108 AC: 375 AN: 3478

EpiCase AF: 0.104

EpiControl AF: 0.103

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 04, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

MMP14-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 16, 2019

This variant is classified as 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	-0.41
CADD	Benign	5.4
DANN	Benign	0.59

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: rs2236302; hg19: chr14-23312554; COSMIC: COSV61287578; COSMIC: COSV61287578;