16-3047452-A-C

Position:

• chr16-3047452-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_022468.5(MMP25):​c.137A>C​(p.His46Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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 Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: MMP25 NM_022468.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.31

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

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.11621094).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MMP25	NM_022468.5	c.137A>C	p.His46Pro	missense_variant	2/10	ENST00000336577.9
MMP25	XM_024450390.2	c.137A>C	p.His46Pro	missense_variant	2/8
MMP25	XM_017023561.2	c.137A>C	p.His46Pro	missense_variant	2/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MMP25	ENST00000336577.9	c.137A>C	p.His46Pro	missense_variant	2/10	1	NM_022468.5	P1
MMP25-AS1	ENST00000576250.6	n.1110+4208T>G		intron_variant, non_coding_transcript_variant		5
MMP25	ENST00000612971.2	c.137A>C	p.His46Pro	missense_variant, NMD_transcript_variant	2/11	5
MMP25-AS1	ENST00000649784.1	n.2175-406T>G		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 16, 2021

The c.137A>C (p.H46P) alteration is located in exon 2 (coding exon 2) of the MMP25 gene. This alteration results from a A to C substitution at nucleotide position 137, causing the histidine (H) at amino acid position 46 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.50
CADD	Uncertain	24
DANN	Benign	0.96
DEOGEN2	Benign	0.071	T
Eigen	Benign	-0.43
Eigen_PC	Benign	-0.33
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Benign	0.79	T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.73	N
MutationTaster	Benign	0.96	N
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.072
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.0070	D
Polyphen		0.0030	B
Vest4		0.29
MutPred		0.47		Gain of glycosylation at H46 (P = 2e-04);
MVP		0.50
MPC		0.65
ClinPred		0.78	D
GERP RS		5.0
Varity_R		0.36
gMVP		0.76

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.19		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr16-3097453;