22-23772875-C-T

Variant names:

• chr22-23772875-C-T
• rs1345948587
• NM_005940.5:c.5C>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_005940.5(MMP11):​c.5C>T​(p.Ala2Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000397 in 1,007,028 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A2D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000040 (0 hom.)
• Consequence: MMP11 NM_005940.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.289
• Publications: 0 publications found

Genes affected

MMP11 (HGNC:7157): (matrix metallopeptidase 11) 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 enzyme encoded by this gene is activated intracellularly by furin within the constitutive secretory pathway. Also in contrast to other MMP's, this enzyme cleaves alpha 1-proteinase inhibitor but weakly degrades structural proteins of the extracellular matrix. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.29007298).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005940.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MMP11	NM_005940.5	MANE Select	c.5C>T	p.Ala2Val	missense	Exon 1 of 8	NP_005931.2	P24347
	MMP11	NR_133013.2		n.27C>T		non_coding_transcript_exon	Exon 1 of 8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MMP11	ENST00000215743.8	TSL:1 MANE Select	c.5C>T	p.Ala2Val	missense	Exon 1 of 8	ENSP00000215743.3	P24347
	MMP11	ENST00000872484.1		c.5C>T	p.Ala2Val	missense	Exon 1 of 8	ENSP00000542543.1
	MMP11	ENST00000872487.1		c.5C>T	p.Ala2Val	missense	Exon 1 of 8	ENSP00000542546.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000397 AC: 4 AN: 1007028 Hom.: 0 Cov.: 28 AF XY: 0.00000421 AC XY: 2 AN XY: 474796

African (AFR) AF: 0.00 AC: 0 AN: 20194

American (AMR) AF: 0.00 AC: 0 AN: 6016

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 11034

East Asian (EAS) AF: 0.00 AC: 0 AN: 19176

South Asian (SAS) AF: 0.00 AC: 0 AN: 18900

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 17470

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2522

European-Non Finnish (NFE) AF: 0.00000458 AC: 4 AN: 873482

Other (OTH) AF: 0.00 AC: 0 AN: 38234

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.077	T
Eigen	Benign	-0.17
Eigen_PC	Benign	-0.17
FATHMM_MKL	Benign	0.41	N
M_CAP	Benign	0.041	D
MetaRNN	Benign	0.29	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		0.29
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-0.84	N
REVEL	Benign	0.082
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.85	P
Vest4		0.23
MutPred		0.26		Loss of glycosylation at P3 (P = 0.0634)
MVP		0.65
MPC		0.32
ClinPred		0.96	D
GERP RS		2.1
PromoterAI		0.63	Over-expression
Varity_R		0.22
gMVP		0.59
Mutation Taster		=87/13	polymorphism

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: rs1345948587; hg19: chr22-24115062;