rs3751489

Positions:

• chr14-22844771-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_004995.4(MMP14):​c.1292G>A​(p.Arg431His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000554 in 1,614,050 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts 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 0.00078 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00053 (5 hom.)
• Consequence: MMP14 NM_004995.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 2.46

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0105009675).
• BP6: Variant 14-22844771-G-A is Benign according to our data. Variant chr14-22844771-G-A is described in ClinVar as [Benign]. Clinvar id is 717373.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000775 (118/152212) while in subpopulation EAS AF= 0.0201 (104/5184). AF 95% confidence interval is 0.0169. There are 1 homozygotes in gnomad4. There are 64 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MMP14	NM_004995.4	c.1292G>A	p.Arg431His	missense_variant	8/10	ENST00000311852.11	NP_004986.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MMP14	ENST00000311852.11	c.1292G>A	p.Arg431His	missense_variant	8/10	1	NM_004995.4	ENSP00000308208.6

Frequencies

GnomAD3 genomes AF: 0.000776 AC: 118 AN: 152094 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0200

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.000957

GnomAD3 exomes AF: 0.00182 AC: 458 AN: 251424 Hom.: 3 AF XY: 0.00160 AC XY: 218 AN XY: 135894

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000579

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0223

Gnomad SAS exome AF: 0.00118

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000528

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.000531 AC: 776 AN: 1461838 Hom.: 5 Cov.: 32 AF XY: 0.000545 AC XY: 396 AN XY: 727220

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0141

Gnomad4 SAS exome AF: 0.00116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000513

Gnomad4 OTH exome AF: 0.000861

GnomAD4 genome AF: 0.000775 AC: 118 AN: 152212 Hom.: 1 Cov.: 32 AF XY: 0.000860 AC XY: 64 AN XY: 74438

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0201

Gnomad4 SAS AF: 0.00145

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.000947

Alfa AF: 0.000675 Hom.: 0

Bravo AF: 0.00113

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00193 AC: 234

Asia WGS AF: 0.00491 AC: 17 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

MMP14-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 13, 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). -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 20, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.13
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.18	T
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.86	D
MetaRNN	Benign	0.011	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.8	M
PrimateAI	Uncertain	0.61	T
PROVEAN	Uncertain	-2.6	D
REVEL	Benign	0.24
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.022	D
Polyphen		1.0	D
Vest4		0.33
MVP		0.67
MPC		0.71
ClinPred		0.14	T
GERP RS		5.2
Varity_R		0.81
gMVP		0.53

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: rs3751489; hg19: chr14-23313980;