rs1042704

Positions:

• chr14-22843385-G-A
• chr14-22843385-G-C

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.817G>A​(p.Asp273Asn) variant causes a missense change. The variant allele was found at a frequency of 0.191 in 1,613,702 control chromosomes in the GnomAD database, including 31,921 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 0.14 (2021 hom., cov: 31)
  • Exomes 𝑓: 0.20 (29900 hom.)
• Consequence: MMP14 NM_004995.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 4.88

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=0.0025402606).
• BP6: Variant 14-22843385-G-A is Benign according to our data. Variant chr14-22843385-G-A is described in ClinVar as [Benign]. Clinvar id is 1237040.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.205 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MMP14	NM_004995.4	c.817G>A	p.Asp273Asn	missense_variant	5/10	ENST00000311852.11	NP_004986.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MMP14	ENST00000311852.11	c.817G>A	p.Asp273Asn	missense_variant	5/10	1	NM_004995.4	ENSP00000308208	P1
MMP14	ENST00000548162.2	c.817G>A	p.Asp273Asn	missense_variant	5/10	5		ENSP00000506068
MMP14	ENST00000680097.1	c.*132G>A		3_prime_UTR_variant, NMD_transcript_variant	5/10			ENSP00000506631
MMP14	ENST00000680941.1	c.*215G>A		3_prime_UTR_variant, NMD_transcript_variant	6/11			ENSP00000506378

Frequencies

GnomAD3 genomes AF: 0.143 AC: 21779 AN: 151996 Hom.: 2020 Cov.: 31

Gnomad AFR AF: 0.0390

Gnomad AMI AF: 0.172

Gnomad AMR AF: 0.117

Gnomad ASJ AF: 0.154

Gnomad EAS AF: 0.0236

Gnomad SAS AF: 0.216

Gnomad FIN AF: 0.205

Gnomad MID AF: 0.136

Gnomad NFE AF: 0.207

Gnomad OTH AF: 0.135

GnomAD3 exomes AF: 0.164 AC: 41229 AN: 251266 Hom.: 4043 AF XY: 0.171 AC XY: 23251 AN XY: 135832

Gnomad AFR exome AF: 0.0356

Gnomad AMR exome AF: 0.105

Gnomad ASJ exome AF: 0.141

Gnomad EAS exome AF: 0.0184

Gnomad SAS exome AF: 0.225

Gnomad FIN exome AF: 0.210

Gnomad NFE exome AF: 0.201

Gnomad OTH exome AF: 0.159

GnomAD4 exome AF: 0.196 AC: 286595 AN: 1461588 Hom.: 29900 Cov.: 34 AF XY: 0.198 AC XY: 143655 AN XY: 727110

Gnomad4 AFR exome AF: 0.0310

Gnomad4 AMR exome AF: 0.105

Gnomad4 ASJ exome AF: 0.143

Gnomad4 EAS exome AF: 0.0163

Gnomad4 SAS exome AF: 0.222

Gnomad4 FIN exome AF: 0.208

Gnomad4 NFE exome AF: 0.211

Gnomad4 OTH exome AF: 0.177

GnomAD4 genome AF: 0.143 AC: 21780 AN: 152114 Hom.: 2021 Cov.: 31 AF XY: 0.142 AC XY: 10567 AN XY: 74360

Gnomad4 AFR AF: 0.0389

Gnomad4 AMR AF: 0.117

Gnomad4 ASJ AF: 0.154

Gnomad4 EAS AF: 0.0230

Gnomad4 SAS AF: 0.216

Gnomad4 FIN AF: 0.205

Gnomad4 NFE AF: 0.207

Gnomad4 OTH AF: 0.137

Alfa AF: 0.181 Hom.: 5711

Bravo AF: 0.128

TwinsUK AF: 0.215 AC: 797

ALSPAC AF: 0.221 AC: 852

ESP6500AA AF: 0.0447 AC: 197

ESP6500EA AF: 0.203 AC: 1747

ExAC AF: 0.164 AC: 19845

Asia WGS AF: 0.139 AC: 484 AN: 3478

EpiCase AF: 0.198

EpiControl AF: 0.198

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 04, 2021	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.73	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	23
DANN	Benign	0.95
DEOGEN2	Benign	0.081	T
Eigen	Benign	-0.13
Eigen_PC	Benign	0.035
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.82	T
MetaRNN	Benign	0.0025	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.6	L
MutationTaster	Benign	0.000010	P
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.085
Sift	Benign	0.41	T
Sift4G	Benign	0.35	T
Polyphen		0.0050	B
Vest4		0.10
MPC		0.31
ClinPred		0.0076	T
GERP RS		5.6
Varity_R		0.39
gMVP		0.49

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1042704; hg19: chr14-23312594; COSMIC: COSV61288047; COSMIC: COSV61288047;