rs2236303

Variant names:

• chr14-22843509-C-T
• rs2236303
• NM_004995.4:c.850+91C>T

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.850+91C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.311 in 1,491,366 control chromosomes in the GnomAD database, including 75,849 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.27 (6518 hom., cov: 31)
  • Exomes 𝑓: 0.32 (69331 hom.)
• Consequence: MMP14 NM_004995.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.270
• Publications: 13 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 14-22843509-C-T is Benign according to our data. Variant chr14-22843509-C-T is described in ClinVar as Benign. ClinVar VariationId is 1271157.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.463 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MMP14	NM_004995.4	c.850+91C>T		intron_variant	Intron 5 of 9	ENST00000311852.11	NP_004986.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MMP14	ENST00000311852.11	c.850+91C>T		intron_variant	Intron 5 of 9	1	NM_004995.4	ENSP00000308208.6
MMP14	ENST00000548162.2	c.850+91C>T		intron_variant	Intron 5 of 9	5		ENSP00000506068.1
MMP14	ENST00000680097.1	n.*165+91C>T		intron_variant	Intron 5 of 9			ENSP00000506631.1
MMP14	ENST00000680941.1	n.*248+91C>T		intron_variant	Intron 6 of 10			ENSP00000506378.1

Frequencies

GnomAD3 genomes AF: 0.268 AC: 40673 AN: 151760 Hom.: 6515 Cov.: 31

Gnomad AFR AF: 0.0909

Gnomad AMI AF: 0.147

Gnomad AMR AF: 0.372

Gnomad ASJ AF: 0.362

Gnomad EAS AF: 0.479

Gnomad SAS AF: 0.257

Gnomad FIN AF: 0.369

Gnomad MID AF: 0.263

Gnomad NFE AF: 0.318

Gnomad OTH AF: 0.274

GnomAD4 exome AF: 0.316 AC: 423005 AN: 1339488 Hom.: 69331 Cov.: 22 AF XY: 0.314 AC XY: 207285 AN XY: 660596

African (AFR) AF: 0.0821 AC: 2525 AN: 30764

American (AMR) AF: 0.480 AC: 18091 AN: 37686

Ashkenazi Jewish (ASJ) AF: 0.379 AC: 8103 AN: 21404

East Asian (EAS) AF: 0.484 AC: 18743 AN: 38730

South Asian (SAS) AF: 0.251 AC: 18790 AN: 74944

European-Finnish (FIN) AF: 0.360 AC: 15349 AN: 42596

Middle Eastern (MID) AF: 0.310 AC: 1641 AN: 5288

European-Non Finnish (NFE) AF: 0.312 AC: 322287 AN: 1032238

Other (OTH) AF: 0.313 AC: 17476 AN: 55838

GnomAD4 genome AF: 0.268 AC: 40681 AN: 151878 Hom.: 6518 Cov.: 31 AF XY: 0.273 AC XY: 20268 AN XY: 74202

African (AFR) AF: 0.0908 AC: 3763 AN: 41434

American (AMR) AF: 0.372 AC: 5671 AN: 15234

Ashkenazi Jewish (ASJ) AF: 0.362 AC: 1256 AN: 3468

East Asian (EAS) AF: 0.479 AC: 2462 AN: 5142

South Asian (SAS) AF: 0.257 AC: 1235 AN: 4804

European-Finnish (FIN) AF: 0.369 AC: 3885 AN: 10536

Middle Eastern (MID) AF: 0.269 AC: 79 AN: 294

European-Non Finnish (NFE) AF: 0.318 AC: 21624 AN: 67950

Other (OTH) AF: 0.272 AC: 572 AN: 2104

Alfa AF: 0.297 Hom.: 11416

Bravo AF: 0.265

Asia WGS AF: 0.336 AC: 1167 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

May 14, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.14
DANN	Benign	0.82
PhyloP100		-0.27
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2236303; hg19: chr14-23312718; COSMIC: COSV61289731; COSMIC: COSV61289731;