Genetic Variant MMP24:p.Pro18Gln (chr20-35226791-C-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_006690.4(MMP24):c.53C>A(p.Pro18Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000165 in 607,148 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 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. P18L) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 34)

Exomes 𝑓: 0.0000016 ( 0 hom. )

Consequence

MMP24
NM_006690.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.0230

Publications

0 publications found

Variant links:

Genes affected

MMP24 (HGNC:7172): (matrix metallopeptidase 24) This gene encodes a member of the peptidase M10 family of matrix metalloproteinases (MMPs). Proteins in this 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. The encoded preproprotein is proteolytically processed to generate the mature protease. Unlike most MMPs, which are secreted, this protease is a member of the membrane-type MMP (MT-MMP) subfamily, contains a transmembrane domain and is expressed at the cell surface. Substrates of this protease include the proteins cadherin 2 and matrix metallopeptidase 2 (also known as 72 kDa type IV collagenase). The gene has previously been referred to as MMP25 but has been renamed matrix metallopeptidase 24 (MMP24). [provided by RefSeq, Oct 2019]

MMP24 links:

MMP24-AS1-EDEM2 (HGNC:):

MMP24-AS1-EDEM2 links:

MMP24OS (HGNC:44421): (MMP24 opposite strand)

MMP24OS links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.094724834).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MMP24	NM_006690.4 link	c.53C>A	p.Pro18Gln	missense_variant	Exon 1 of 9	ENST00000246186.8	NP_006681.1	Q9Y5R2Q86VV6
MMP24	XM_017027597.2 link	c.53C>A	p.Pro18Gln	missense_variant	Exon 1 of 8		XP_016883086.1
MMP24	XM_011528500.3 link	c.53C>A	p.Pro18Gln	missense_variant	Exon 1 of 8		XP_011526802.1
MMP24-AS1-EDEM2	NM_001355008.2 link	c.-351-8730G>T		intron_variant	Intron 3 of 14		NP_001341937.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MMP24	ENST00000246186.8 link	c.53C>A	p.Pro18Gln	missense_variant	Exon 1 of 9	1	NM_006690.4	ENSP00000246186.6		Q9Y5R2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000165

AC:

AN:

607148

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

281222

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

15064

American (AMR)

AF:

0.00

AC:

AN:

712

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3994

East Asian (EAS)

AF:

0.00

AC:

AN:

2468

South Asian (SAS)

AF:

0.0000733

AC:

AN:

13640

European-Finnish (FIN)

AF:

0.00

AC:

AN:

194

Middle Eastern (MID)

AF:

0.00

AC:

AN:

1254

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

549806

Other (OTH)

AF:

0.00

AC:

AN:

20016

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

0.0065

BayesDel_noAF

Benign

-0.23

CADD

Benign

(source)

DANN

Benign

0.90

DEOGEN2

Benign

0.049

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.0018

LIST_S2

Benign

0.20

M_CAP

Uncertain

0.21

MetaRNN

Benign

0.095

MetaSVM

Benign

-0.86

MutationAssessor

Benign

0.0

PhyloP100

0.023

PrimateAI

Uncertain

0.54

PROVEAN

Benign

0.35

REVEL

Benign

0.28

Sift

Pathogenic

0.0

Sift4G

Benign

0.33

Polyphen

0.0

Vest4

0.30

MutPred

0.25

Loss of glycosylation at P18 (P = 4e-04);

MVP

0.41

MPC

0.50

ClinPred

0.15

PromoterAI

0.00010

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.15

gMVP

0.25

Mutation Taster

=99/1

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over