20-35226962-C-G

Variant names:

• chr20-35226962-C-G
• rs1325793538
• NM_006690.4:c.224C>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_006690.4(MMP24):​c.224C>G​(p.Ala75Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000012 in 834,486 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 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. A75T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 29)
  • Exomes 𝑓: 0.0000012 (0 hom.)
• Consequence: MMP24 NM_006690.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0570
• Publications: 0 publications found

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-AS1-EDEM2 (HGNC:):

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

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06156388).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006690.4. 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
	MMP24	NM_006690.4	MANE Select	c.224C>G	p.Ala75Gly	missense	Exon 1 of 9	NP_006681.1	Q9Y5R2
	MMP24-AS1-EDEM2	NM_001355008.2		c.-351-8901G>C		intron	N/A	NP_001341937.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MMP24	ENST00000246186.8	TSL:1 MANE Select	c.224C>G	p.Ala75Gly	missense	Exon 1 of 9	ENSP00000246186.6	Q9Y5R2
	MMP24	ENST00000927316.1		c.224C>G	p.Ala75Gly	missense	Exon 1 of 8	ENSP00000597375.1
	MMP24	ENST00000927315.1		c.224C>G	p.Ala75Gly	missense	Exon 1 of 8	ENSP00000597374.1

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome AF: 0.00000120 AC: 1 AN: 834486 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 385524

African (AFR) AF: 0.00 AC: 0 AN: 15792

American (AMR) AF: 0.00 AC: 0 AN: 1008

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 5160

East Asian (EAS) AF: 0.00 AC: 0 AN: 3648

South Asian (SAS) AF: 0.00 AC: 0 AN: 17304

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 290

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1626

European-Non Finnish (NFE) AF: 0.00000131 AC: 1 AN: 762326

Other (OTH) AF: 0.00 AC: 0 AN: 27332

GnomAD4 genome Cov.: 29

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	14
DANN	Benign	0.95
DEOGEN2	Benign	0.098	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.0080	N
LIST_S2	Benign	0.29	T
M_CAP	Benign	0.037	D
MetaRNN	Benign	0.062	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.14	N
PhyloP100		0.057
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-0.60	N
REVEL	Benign	0.0080
Sift	Benign	0.28	T
Sift4G	Benign	0.14	T
Polyphen		0.030	B
Vest4		0.085
MutPred		0.38		Gain of helix (P = 0.0078)
MVP		0.22
MPC		0.54
ClinPred		0.074	T
GERP RS		-0.10
PromoterAI		-0.085	Neutral
Varity_R		0.064
gMVP		0.28
Mutation Taster		=91/9	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs1325793538; hg19: chr20-33814765;