dbSNP rs2039736075: MMP14:p.Gly26Ser (chr14-22836893-G-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_004995.4(MMP14):c.76G>A(p.Gly26Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,436 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G26V) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

MMP14
NM_004995.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.0770

Publications

0 publications found

Variant links:

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, Labcorp Genetics (formerly Invitae), Ambry Genetics
multicentric osteolysis-nodulosis-arthropathy spectrum
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

MMP14 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.05203232).

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.76G>A	p.Gly26Ser	missense	Exon 1 of 10	NP_004986.1	P50281

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MMP14	ENST00000311852.11	TSL:1 MANE Select	c.76G>A	p.Gly26Ser	missense	Exon 1 of 10	ENSP00000308208.6	P50281
MMP14	ENST00000928197.1		c.76G>A	p.Gly26Ser	missense	Exon 1 of 10	ENSP00000598256.1
MMP14	ENST00000548162.2	TSL:5	c.76G>A	p.Gly26Ser	missense	Exon 1 of 10	ENSP00000506068.1	A0A7P0TAG0

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461436

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727060

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33470

American (AMR)

AF:

0.00

AC:

AN:

44706

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26106

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39688

South Asian (SAS)

AF:

0.00

AC:

AN:

86226

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53342

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111776

Other (OTH)

AF:

0.00

AC:

AN:

60354

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

ClinVar submissions as Germline

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.081

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Benign

-0.51

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.050

Eigen

Benign

-0.79

Eigen_PC

Benign

-0.60

FATHMM_MKL

Benign

0.25

LIST_S2

Benign

0.62

M_CAP

Benign

0.016

MetaRNN

Benign

0.052

MetaSVM

Benign

-0.93

MutationAssessor

Benign

0.0

PhyloP100

0.077

PrimateAI

Uncertain

0.51

PROVEAN

Benign

-0.22

REVEL

Benign

0.10

Sift

Benign

0.64

Sift4G

Benign

0.66

Polyphen

0.0

Vest4

0.083

MutPred

0.24

Gain of phosphorylation at G26 (P = 0.0222)

MVP

0.46

MPC

0.66

ClinPred

0.085

GERP RS

1.3

PromoterAI

-0.010

Neutral

(source)

Varity_R

0.041

gMVP

0.43

Mutation Taster

=90/10

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over