chr16-3050128-C-T

Variant names:

• chr16-3050128-C-T
• rs149856253
• NM_022468.5:c.352C>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_022468.5(MMP25):​c.352C>T​(p.Arg118*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000448 in 1,606,278 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.00033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00046 (2 hom.)
• Consequence: MMP25 NM_022468.5 stop_gained
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 0.399

Genes affected

MMP25 (HGNC:14246): (matrix metallopeptidase 25) 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 MMPs 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, attached to the plasma membrane via a glycosylphosphatidyl inositol anchor. In response to bacterial infection or inflammation, the encoded protein is thought to inactivate alpha-1 proteinase inhibitor, a major tissue protectant against proteolytic enzymes released by activated neutrophils, facilitating the transendothelial migration of neutrophils to inflammatory sites. The encoded protein may also play a role in tumor invasion and metastasis through activation of MMP2. The gene has previously been referred to as MMP20 but has been renamed MMP25. [provided by RefSeq, Jul 2008]

MMP25-AS1 (HGNC:51372): (MMP25 antisense RNA 1)

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MMP25	NM_022468.5	c.352C>T	p.Arg118*	stop_gained	Exon 3 of 10	ENST00000336577.9	NP_071913.1
MMP25	XM_024450391.2	c.250C>T	p.Arg84*	stop_gained	Exon 2 of 9		XP_024306159.1
MMP25	XM_017023561.2	c.352C>T	p.Arg118*	stop_gained	Exon 3 of 6		XP_016879050.1
MMP25	XM_024450390.2	c.232+2581C>T		intron_variant	Intron 2 of 7		XP_024306158.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MMP25	ENST00000336577.9	c.352C>T	p.Arg118*	stop_gained	Exon 3 of 10	1	NM_022468.5	ENSP00000337816.4

Frequencies

GnomAD3 genomes AF: 0.000329 AC: 50 AN: 152186 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000603

Gnomad OTH AF: 0.000956

GnomAD2 exomes AF: 0.000362 AC: 90 AN: 248962 AF XY: 0.000431

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000435

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000483

Gnomad NFE exome AF: 0.000550

Gnomad OTH exome AF: 0.000329

GnomAD4 exome AF: 0.000460 AC: 669 AN: 1453974 Hom.: 2 Cov.: 33 AF XY: 0.000453 AC XY: 327 AN XY: 721836

Gnomad4 AFR exome AF: 0.000150 AC: 5 AN: 33348

Gnomad4 AMR exome AF: 0.000404 AC: 18 AN: 44532

Gnomad4 ASJ exome AF: 0.0000384 AC: 1 AN: 26014

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 39442

Gnomad4 SAS exome AF: 0.000198 AC: 17 AN: 86052

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 52040

Gnomad4 NFE exome AF: 0.000547 AC: 605 AN: 1106740

Gnomad4 Remaining exome AF: 0.000350 AC: 21 AN: 60056

GnomAD4 genome AF: 0.000328 AC: 50 AN: 152304 Hom.: 0 Cov.: 32 AF XY: 0.000363 AC XY: 27 AN XY: 74472

Gnomad4 AFR AF: 0.0000241 AC: 0.000024057 AN: 0.000024057

Gnomad4 AMR AF: 0.000261 AC: 0.000261472 AN: 0.000261472

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.000193 AC: 0.000193125 AN: 0.000193125

Gnomad4 SAS AF: 0.000207 AC: 0.000207039 AN: 0.000207039

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.000603 AC: 0.000602817 AN: 0.000602817

Gnomad4 OTH AF: 0.000946 AC: 0.000946074 AN: 0.000946074

Alfa AF: 0.000508 Hom.: 0

Bravo AF: 0.000370

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.000379 AC: 46

EpiCase AF: 0.000545

EpiControl AF: 0.00107

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

Mendelian syndromes with cleft lip/palate Uncertain:1

-

Faculty of Pharmacy, University of Ljubljana

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Pathogenic	0.45
CADD	Pathogenic	43
DANN	Uncertain	1.0
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Benign	0.34	N
Vest4		0.58
GERP RS		4.0
Mutation Taster		=40/160	disease causing (fs/PTC)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs149856253; hg19: chr16-3100129;