20-35226880-G-A

Variant names:

Variant summary

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

The NM_006690.4(MMP24):c.142G>A(p.Gly48Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000691 in 144,764 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. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000069 ( 0 hom., cov: 29)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

MMP24
NM_006690.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.41

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:

Genome browser will be placed here

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=0.15345517).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MMP24	NM_006690.4 link	c.142G>A	p.Gly48Ser	missense_variant	Exon 1 of 9	ENST00000246186.8	NP_006681.1	Q9Y5R2Q86VV6
MMP24	XM_017027597.2 link	c.142G>A	p.Gly48Ser	missense_variant	Exon 1 of 8		XP_016883086.1
MMP24	XM_011528500.3 link	c.142G>A	p.Gly48Ser	missense_variant	Exon 1 of 8		XP_011526802.1
MMP24-AS1-EDEM2	NM_001355008.2 link	c.-351-8819C>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.142G>A	p.Gly48Ser	missense_variant	Exon 1 of 9	1	NM_006690.4	ENSP00000246186.6		Q9Y5R2

Frequencies

GnomAD3 genomes

AF:

0.00000691

AC:

AN:

144764

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000153

Gnomad OTH

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

835574

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

386356

African (AFR)

AF:

0.00

AC:

AN:

15824

American (AMR)

AF:

0.00

AC:

AN:

1008

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

5166

East Asian (EAS)

AF:

0.00

AC:

AN:

3708

South Asian (SAS)

AF:

0.00

AC:

AN:

17318

European-Finnish (FIN)

AF:

0.00

AC:

AN:

292

Middle Eastern (MID)

AF:

0.00

AC:

AN:

1624

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

763290

Other (OTH)

AF:

0.00

AC:

AN:

27344

GnomAD4 genome

AF:

0.00000691

AC:

AN:

144764

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

70334

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

40394

American (AMR)

AF:

0.00

AC:

AN:

14666

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3386

East Asian (EAS)

AF:

0.00

AC:

AN:

4906

South Asian (SAS)

AF:

0.00

AC:

AN:

4776

European-Finnish (FIN)

AF:

0.00

AC:

AN:

8158

Middle Eastern (MID)

AF:

0.00

AC:

AN:

308

European-Non Finnish (NFE)

AF:

0.0000153

AC:

AN:

65272

Other (OTH)

AF:

0.00

AC:

AN:

2000

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 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: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

May 21, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.142G>A (p.G48S) alteration is located in exon (coding exon ) of the MMP24 gene. This alteration results from a G to A substitution at nucleotide position 142, causing the glycine (G) at amino acid position 48 to be replaced by a serine (S). 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

0.16

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.63

CADD

Benign

(source)

DANN

Benign

0.94

DEOGEN2

Benign

0.042

Eigen

Benign

-0.59

Eigen_PC

Benign

-0.74

FATHMM_MKL

Benign

0.0036

LIST_S2

Benign

0.38

M_CAP

Benign

0.046

MetaRNN

Benign

0.15

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

PhyloP100

1.4

PrimateAI

Uncertain

0.55

PROVEAN

Benign

0.26

REVEL

Benign

0.082

Sift

Benign

0.80

Sift4G

Benign

0.37

Polyphen

0.98

Vest4

0.16

MutPred

0.36

Gain of glycosylation at G48 (P = 0.0143);

MVP

0.35

MPC

0.54

ClinPred

0.22

PromoterAI

-0.064

Neutral

(source)

Varity_R

0.10

gMVP

0.22

Mutation Taster

=91/9

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over