20-35246955-C-T

Variant names:

• chr20-35246955-C-T
• rs765314360
• NM_006690.4:c.362C>T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_006690.4(MMP24):​c.362C>T​(p.Pro121Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000223 in 1,614,052 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000020 (0 hom.)
• Consequence: MMP24 NM_006690.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.14

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

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3775525).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MMP24	NM_006690.4	c.362C>T	p.Pro121Leu	missense_variant	Exon 2 of 9	ENST00000246186.8	NP_006681.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MMP24	ENST00000246186.8	c.362C>T	p.Pro121Leu	missense_variant	Exon 2 of 9	1	NM_006690.4	ENSP00000246186.6

Frequencies

GnomAD3 genomes AF: 0.0000460 AC: 7 AN: 152224 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000321 AC: 8 AN: 249264 Hom.: 0 AF XY: 0.0000148 AC XY: 2 AN XY: 135224

Gnomad AFR exome AF: 0.000129

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000223

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000885

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000198 AC: 29 AN: 1461710 Hom.: 0 Cov.: 32 AF XY: 0.0000234 AC XY: 17 AN XY: 727138

Gnomad4 AFR exome AF: 0.000119

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000153

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome AF: 0.0000459 AC: 7 AN: 152342 Hom.: 0 Cov.: 32 AF XY: 0.0000268 AC XY: 2 AN XY: 74500

Gnomad4 AFR AF: 0.000144

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000354 Hom.: 0

Bravo AF: 0.0000529

ExAC AF: 0.0000248 AC: 3

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 21, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.362C>T (p.P121L) alteration is located in exon 2 (coding exon 2) of the MMP24 gene. This alteration results from a C to T substitution at nucleotide position 362, causing the proline (P) at amino acid position 121 to be replaced by a leucine (L). 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	0.26
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.13
CADD	Uncertain	24
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.41	T
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.034	D
MetaRNN	Benign	0.38	T
MetaSVM	Benign	-0.83	T
MutationAssessor	Pathogenic	3.7	H
PrimateAI	Pathogenic	0.81	D
PROVEAN	Uncertain	-3.1	D
REVEL	Benign	0.13
Sift	Benign	0.045	D
Sift4G	Benign	0.23	T
Polyphen		0.67	P
Vest4		0.47
MVP		0.75
MPC		1.5
ClinPred		0.87	D
GERP RS		5.5
Varity_R		0.22
gMVP		0.74

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs765314360; hg19: chr20-33834758; COSMIC: COSV105820107;