NM_004995.4:c.-364G>T

Variant names:

• chr14-22836454-G-T
• rs1003349
• NM_004995.4:c.-364G>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

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. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.30 (7000 hom., cov: 28)
  • Exomes 𝑓: 0.22 (1633 hom.)
• Consequence: MMP14 NM_004995.4 upstream_gene
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.556
• Publications: 28 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
• multicentric osteolysis-nodulosis-arthropathy spectrum

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 14-22836454-G-T is Benign according to our data. Variant chr14-22836454-G-T is described in ClinVar as Benign. ClinVar VariationId is 1297228.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.407 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MMP14	NM_004995.4	MANE Select	c.-364G>T		upstream_gene	N/A	NP_004986.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MMP14	ENST00000311852.11	TSL:1 MANE Select	c.-364G>T		upstream_gene	N/A	ENSP00000308208.6
	MMP14	ENST00000548162.2	TSL:5	c.-364G>T		upstream_gene	N/A	ENSP00000506068.1
	MMP14	ENST00000547074.1	TSL:2	n.-106G>T		upstream_gene	N/A

Frequencies

GnomAD3 genomes AF: 0.297 AC: 44369 AN: 149290 Hom.: 7003 Cov.: 28

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

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: 98 AN: 622

European-Finnish (FIN) AF: 0.237 AC: 928 AN: 3920

Middle Eastern (MID) AF: 0.212 AC: 69 AN: 326

European-Non Finnish (NFE) AF: 0.209 AC: 7922 AN: 37916

Other (OTH) AF: 0.212 AC: 777 AN: 3664

GnomAD4 genome AF: 0.297 AC: 44380 AN: 149404 Hom.: 7000 Cov.: 28 AF XY: 0.303 AC XY: 22061 AN XY: 72694

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: 97 AN: 292

European-Non Finnish (NFE) AF: 0.299 AC: 20169 AN: 67426

Other (OTH) AF: 0.313 AC: 648 AN: 2070

Alfa AF: 0.306 Hom.: 14701

Bravo AF: 0.300

Asia WGS AF: 0.347 AC: 1202 AN: 3470

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	8.2
DANN	Benign	0.62
PhyloP100		0.56
PromoterAI		-0.14	Neutral

Splicing

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

Other links and lift over

dbSNP: rs1003349; hg19: chr14-23305663;