14-22843345-C-G

Variant names:

• chr14-22843345-C-G
• rs2236302
• NM_004995.4:c.777C>G

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_004995.4(MMP14):​c.777C>G​(p.Pro259Pro) 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 NM_004995.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.469
• Publications: 32 publications found

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]

MMP14 Gene-Disease associations (from GenCC):

• Winchester syndrome

  Inheritance: AR, Unknown Classification: MODERATE, LIMITED Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• multicentric osteolysis-nodulosis-arthropathy spectrum

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004995.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MMP14	NM_004995.4	MANE Select	c.777C>G	p.Pro259Pro	synonymous	Exon 5 of 10	NP_004986.1	P50281

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MMP14	ENST00000311852.11	TSL:1 MANE Select	c.777C>G	p.Pro259Pro	synonymous	Exon 5 of 10	ENSP00000308208.6	P50281
	MMP14	ENST00000928197.1		c.591C>G	p.Pro197Pro	synonymous	Exon 5 of 10	ENSP00000598256.1
	MMP14	ENST00000548162.2	TSL:5	c.777C>G	p.Pro259Pro	synonymous	Exon 5 of 10	ENSP00000506068.1	A0A7P0TAG0

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

GnomAD2 exomes AF: 0.123 AC: 30878 AN: 251318 AF XY: 0.116

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 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

African (AFR) AF: 0.294 AC: 9848 AN: 33468

American (AMR) AF: 0.150 AC: 6721 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.103 AC: 2686 AN: 26128

East Asian (EAS) AF: 0.120 AC: 4770 AN: 39692

South Asian (SAS) AF: 0.0667 AC: 5748 AN: 86238

European-Finnish (FIN) AF: 0.107 AC: 5727 AN: 53348

Middle Eastern (MID) AF: 0.108 AC: 624 AN: 5768

European-Non Finnish (NFE) AF: 0.104 AC: 116015 AN: 1111902

Other (OTH) AF: 0.116 AC: 7021 AN: 60386

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

African (AFR) AF: 0.285 AC: 11806 AN: 41418

American (AMR) AF: 0.139 AC: 2130 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.109 AC: 378 AN: 3470

East Asian (EAS) AF: 0.128 AC: 660 AN: 5144

South Asian (SAS) AF: 0.0686 AC: 331 AN: 4826

European-Finnish (FIN) AF: 0.105 AC: 1114 AN: 10594

Middle Eastern (MID) AF: 0.126 AC: 37 AN: 294

European-Non Finnish (NFE) AF: 0.105 AC: 7160 AN: 67990

Other (OTH) AF: 0.165 AC: 349 AN: 2114

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	MMP14-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.41
CADD	Benign	5.4
DANN	Benign	0.59
PhyloP100		-0.47
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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