rs2236303

Positions:

• chr14-22843509-C-T

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.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

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 (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 id 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/exons	MANE	Protein	UniProt
MMP14	NM_004995.4	c.850+91C>T		intron_variant		ENST00000311852.11	NP_004986.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MMP14	ENST00000311852.11	c.850+91C>T		intron_variant		1	NM_004995.4	ENSP00000308208.6
MMP14	ENST00000548162.2	c.850+91C>T		intron_variant		5		ENSP00000506068.1
MMP14	ENST00000680097.1	n.*165+91C>T		intron_variant				ENSP00000506631.1
MMP14	ENST00000680941.1	n.*248+91C>T		intron_variant				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

Gnomad4 AFR exome AF: 0.0821

Gnomad4 AMR exome AF: 0.480

Gnomad4 ASJ exome AF: 0.379

Gnomad4 EAS exome AF: 0.484

Gnomad4 SAS exome AF: 0.251

Gnomad4 FIN exome AF: 0.360

Gnomad4 NFE exome AF: 0.312

Gnomad4 OTH exome AF: 0.313

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

Gnomad4 AFR AF: 0.0908

Gnomad4 AMR AF: 0.372

Gnomad4 ASJ AF: 0.362

Gnomad4 EAS AF: 0.479

Gnomad4 SAS AF: 0.257

Gnomad4 FIN AF: 0.369

Gnomad4 NFE AF: 0.318

Gnomad4 OTH AF: 0.272

Alfa AF: 0.296 Hom.: 1708

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

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 14, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.14
DANN	Benign	0.82

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