chr14-22836867-C-G

Variant names:

• chr14-22836867-C-G
• rs587777039
• NM_004995.4:c.50C>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PM2 PP5 BP4

The NM_004995.4(MMP14):​c.50C>G​(p.Thr17Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MMP14 NM_004995.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 2.08
• Publications: 3 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
• multicentric osteolysis-nodulosis-arthropathy spectrum

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 14-22836867-C-G is Pathogenic according to our data. Variant chr14-22836867-C-G is described in ClinVar as Pathogenic. ClinVar VariationId is 65463.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.20005849). . Strength limited to SUPPORTING due to the PP5.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MMP14	NM_004995.4	MANE Select	c.50C>G	p.Thr17Arg	missense	Exon 1 of 10	NP_004986.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MMP14	ENST00000311852.11	TSL:1 MANE Select	c.50C>G	p.Thr17Arg	missense	Exon 1 of 10	ENSP00000308208.6
	MMP14	ENST00000548162.2	TSL:5	c.50C>G	p.Thr17Arg	missense	Exon 1 of 10	ENSP00000506068.1
	MMP14	ENST00000547074.1	TSL:2	n.308C>G		non_coding_transcript_exon	Exon 1 of 2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Winchester syndrome Pathogenic:1

Sep 07, 2012

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	0.0051	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	20
DANN	Benign	0.92
DEOGEN2	Benign	0.11	T
Eigen	Benign	-0.52
Eigen_PC	Benign	-0.31
FATHMM_MKL	Benign	0.74	D
LIST_S2	Benign	0.30	T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.20	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
PhyloP100		2.1
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-0.82	N
REVEL	Benign	0.27
Sift	Benign	0.056	T
Sift4G	Benign	0.36	T
Polyphen		0.020	B
Vest4		0.46
MutPred		0.40		Gain of methylation at T17 (P = 0.031)
MVP		0.92
MPC		0.76
ClinPred		0.30	T
GERP RS		3.7
PromoterAI		-0.0074	Neutral
Varity_R		0.24
gMVP		0.54
Mutation Taster		=27/73	disease causing (ClinVar)

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: rs587777039; hg19: chr14-23306076;