rs1042704

Variant names:

• chr14-22843385-G-A
• rs1042704
• NM_004995.4:c.817G>A

Your query was ambiguous. Multiple possible variants found:

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

Variant summary

Our verdict is Benign. The variant received -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. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D273G) has been classified as Uncertain significance.

• 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
• Publications: 65 publications found

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

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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.

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.817G>A	p.Asp273Asn	missense	Exon 5 of 10	NP_004986.1	P50281

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MMP14	ENST00000311852.11	TSL:1 MANE Select	c.817G>A	p.Asp273Asn	missense	Exon 5 of 10	ENSP00000308208.6	P50281
	MMP14	ENST00000928197.1		c.631G>A	p.Asp211Asn	missense	Exon 5 of 10	ENSP00000598256.1
	MMP14	ENST00000548162.2	TSL:5	c.817G>A	p.Asp273Asn	missense	Exon 5 of 10	ENSP00000506068.1	A0A7P0TAG0

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

GnomAD2 exomes AF: 0.164 AC: 41229 AN: 251266 AF XY: 0.171

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 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

African (AFR) AF: 0.0310 AC: 1037 AN: 33480

American (AMR) AF: 0.105 AC: 4680 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.143 AC: 3743 AN: 26130

East Asian (EAS) AF: 0.0163 AC: 649 AN: 39700

South Asian (SAS) AF: 0.222 AC: 19166 AN: 86248

European-Finnish (FIN) AF: 0.208 AC: 11097 AN: 53254

Middle Eastern (MID) AF: 0.142 AC: 818 AN: 5768

European-Non Finnish (NFE) AF: 0.211 AC: 234722 AN: 1111902

Other (OTH) AF: 0.177 AC: 10683 AN: 60390

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

African (AFR) AF: 0.0389 AC: 1616 AN: 41520

American (AMR) AF: 0.117 AC: 1782 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.154 AC: 533 AN: 3472

East Asian (EAS) AF: 0.0230 AC: 119 AN: 5164

South Asian (SAS) AF: 0.216 AC: 1041 AN: 4812

European-Finnish (FIN) AF: 0.205 AC: 2164 AN: 10572

Middle Eastern (MID) AF: 0.129 AC: 38 AN: 294

European-Non Finnish (NFE) AF: 0.207 AC: 14041 AN: 67974

Other (OTH) AF: 0.137 AC: 289 AN: 2112

Alfa AF: 0.180 Hom.: 10636

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

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		4.9
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
Mutation Taster		=79/21	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1042704; hg19: chr14-23312594; COSMIC: COSV61288047; COSMIC: COSV61288047;