14-22836839-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004995.4(MMP14):c.22C>T(p.Pro8Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.844 in 1,611,232 control chromosomes in the GnomAD database, including 575,345 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.85 (54474 hom., cov: 30)
  • Exomes 𝑓: 0.84 (520871 hom.)
• Consequence: MMP14 NM_004995.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.424

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=7.0322017E-7).
• BP6: Variant 14-22836839-C-T is Benign according to our data. Variant chr14-22836839-C-T is described in ClinVar as [Benign]. Clinvar id is 1279198.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.974 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MMP14	NM_004995.4	c.22C>T	p.Pro8Ser	missense_variant	1/10	ENST00000311852.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MMP14	ENST00000311852.11	c.22C>T	p.Pro8Ser	missense_variant	1/10	1	NM_004995.4	P1

Frequencies

GnomAD3 genomes AF: 0.846 AC: 128389 AN: 151806 Hom.: 54425 Cov.: 30

Gnomad AFR AF: 0.830

Gnomad AMI AF: 0.668

Gnomad AMR AF: 0.854

Gnomad ASJ AF: 0.835

Gnomad EAS AF: 0.997

Gnomad SAS AF: 0.782

Gnomad FIN AF: 0.883

Gnomad MID AF: 0.810

Gnomad NFE AF: 0.844

Gnomad OTH AF: 0.847

GnomAD3 exomes AF: 0.856 AC: 209568 AN: 244772 Hom.: 90065 AF XY: 0.849 AC XY: 112883 AN XY: 132986

Gnomad AFR exome AF: 0.831

Gnomad AMR exome AF: 0.885

Gnomad ASJ exome AF: 0.834

Gnomad EAS exome AF: 0.998

Gnomad SAS exome AF: 0.774

Gnomad FIN exome AF: 0.880

Gnomad NFE exome AF: 0.847

Gnomad OTH exome AF: 0.851

GnomAD4 exome AF: 0.844 AC: 1231649 AN: 1459308 Hom.: 520871 Cov.: 42 AF XY: 0.842 AC XY: 610839 AN XY: 725830

Gnomad4 AFR exome AF: 0.836

Gnomad4 AMR exome AF: 0.882

Gnomad4 ASJ exome AF: 0.832

Gnomad4 EAS exome AF: 0.999

Gnomad4 SAS exome AF: 0.769

Gnomad4 FIN exome AF: 0.878

Gnomad4 NFE exome AF: 0.842

Gnomad4 OTH exome AF: 0.845

GnomAD4 genome AF: 0.846 AC: 128497 AN: 151924 Hom.: 54474 Cov.: 30 AF XY: 0.847 AC XY: 62904 AN XY: 74262

Gnomad4 AFR AF: 0.830

Gnomad4 AMR AF: 0.854

Gnomad4 ASJ AF: 0.835

Gnomad4 EAS AF: 0.997

Gnomad4 SAS AF: 0.783

Gnomad4 FIN AF: 0.883

Gnomad4 NFE AF: 0.844

Gnomad4 OTH AF: 0.849

Alfa AF: 0.844 Hom.: 64955

Bravo AF: 0.846

TwinsUK AF: 0.831 AC: 3083

ALSPAC AF: 0.838 AC: 3230

ESP6500AA AF: 0.825 AC: 3636

ESP6500EA AF: 0.839 AC: 7214

ExAC AF: 0.851 AC: 103129

Asia WGS AF: 0.919 AC: 3196 AN: 3478

EpiCase AF: 0.839

EpiControl AF: 0.845

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 19, 2019	- -

MMP14-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 09, 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
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.71	T
BayesDel_noAF	Benign	-0.65
Cadd	Benign	11
Dann	Benign	0.97
DEOGEN2	Benign	0.048	T
Eigen	Benign	-0.97
Eigen_PC	Benign	-0.82
FATHMM_MKL	Benign	0.029	N
LIST_S2	Benign	0.12	T
MetaRNN	Benign	7.0e-7	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.0	N
MutationTaster	Benign	1.0	P
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	0.68	N
REVEL	Benign	0.062
Sift	Benign	1.0	T
Sift4G	Benign	0.93	T
Polyphen		0.0	B
Vest4		0.025
MPC		0.67
ClinPred		0.0051	T
GERP RS		2.5
Varity_R		0.028
gMVP		0.29

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: rs1042703; hg19: chr14-23306048; COSMIC: COSV61289051; COSMIC: COSV61289051;