Genetic Variant MMP14:c.-364G>T (chr14-22836454-G-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_004995.4(MMP14):c.-364G>T variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.277 in 205,110 control chromosomes in the GnomAD database, including 8,633 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.30 ( 7000 hom., cov: 28)

Exomes 𝑓: 0.22 ( 1633 hom. )

Consequence

MMP14
NM_004995.4 upstream_gene

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.556

Publications

28 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
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: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.8).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.407 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MMP14	NM_004995.4 link	c.-364G>T		upstream_gene_variant		ENST00000311852.11	NP_004986.1	P50281

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MMP14	ENST00000311852.11 link	c.-364G>T		upstream_gene_variant		1	NM_004995.4	ENSP00000308208.6		P50281

Frequencies

GnomAD3 genomes

AF:

0.297

AC:

44369

AN:

149290

Hom.:

7003

Cov.:

show subpopulations

Gnomad AFR

AF:

0.214

Gnomad AMI

AF:

0.210

Gnomad AMR

AF:

0.411

Gnomad ASJ

AF:

0.398

Gnomad EAS

AF:

0.423

Gnomad SAS

AF:

0.294

Gnomad FIN

AF:

0.358

Gnomad MID

AF:

0.318

Gnomad NFE

AF:

0.299

Gnomad OTH

AF:

0.317

GnomAD4 exome

AF:

0.222

AC:

12355

AN:

55706

Hom.:

1633

AF XY:

0.224

AC XY:

6430

AN XY:

28706

show subpopulations

African (AFR)

AF:

0.148

AC:

302

AN:

2040

American (AMR)

AF:

0.332

AC:

482

AN:

1452

Ashkenazi Jewish (ASJ)

AF:

0.272

AC:

543

AN:

2000

East Asian (EAS)

AF:

0.328

AC:

1234

AN:

3766

South Asian (SAS)

AF:

0.158

AC:

AN:

622

European-Finnish (FIN)

AF:

0.237

AC:

928

AN:

3920

Middle Eastern (MID)

AF:

0.212

AC:

AN:

326

European-Non Finnish (NFE)

AF:

0.209

AC:

7922

AN:

37916

Other (OTH)

AF:

0.212

AC:

777

AN:

3664

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

Heterozygous variant carriers

424

847

1271

1694

2118

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.297

AC:

44380

AN:

149404

Hom.:

7000

Cov.:

AF XY:

0.303

AC XY:

22061

AN XY:

72694

show subpopulations

African (AFR)

AF:

0.214

AC:

8700

AN:

40666

American (AMR)

AF:

0.411

AC:

6149

AN:

14956

Ashkenazi Jewish (ASJ)

AF:

0.398

AC:

1380

AN:

3464

East Asian (EAS)

AF:

0.422

AC:

2141

AN:

5074

South Asian (SAS)

AF:

0.294

AC:

1393

AN:

4740

European-Finnish (FIN)

AF:

0.358

AC:

3513

AN:

9810

Middle Eastern (MID)

AF:

0.332

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.299

AC:

20169

AN:

67426

Other (OTH)

AF:

0.313

AC:

648

AN:

2070

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

1362

2724

4087

5449

6811

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.306

Hom.:

14701

Bravo

AF:

0.300

Asia WGS

AF:

0.347

AC:

1202

AN:

3470

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

May 14, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 18927121) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.80

CADD

Benign

8.2

(source)

DANN

Benign

0.62

PhyloP100

0.56

PromoterAI

-0.14

Neutral

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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14-22836454-G-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over