chr20-35226962-C-T

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_006690.4(MMP24):​c.224C>T​(p.Ala75Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000163 in 979,830 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. Variant has been reported in ClinVar as Uncertain significance (★). 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: 𝑓 0.000034 (0 hom., cov: 29)
  • Exomes 𝑓: 0.000013 (0 hom.)
• Consequence: MMP24 NM_006690.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• 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: 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=0.068798125).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MMP24	NM_006690.4	c.224C>T	p.Ala75Val	missense_variant	Exon 1 of 9	ENST00000246186.8	NP_006681.1
MMP24	XM_017027597.2	c.224C>T	p.Ala75Val	missense_variant	Exon 1 of 8		XP_016883086.1
MMP24	XM_011528500.3	c.224C>T	p.Ala75Val	missense_variant	Exon 1 of 8		XP_011526802.1
MMP24-AS1-EDEM2	NM_001355008.2	c.-351-8901G>A		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	c.224C>T	p.Ala75Val	missense_variant	Exon 1 of 9	1	NM_006690.4	ENSP00000246186.6

Frequencies

GnomAD3 genomes AF: 0.0000344 AC: 5 AN: 145344 Hom.: 0 Cov.: 29

Gnomad AFR AF: 0.0000986

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 AF: 0.0000132 AC: 11 AN: 834486 Hom.: 0 Cov.: 31 AF XY: 0.00000778 AC XY: 3 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: 0.0000131 AC: 10 AN: 762326

Other (OTH) AF: 0.0000366 AC: 1 AN: 27332

GnomAD4 genome AF: 0.0000344 AC: 5 AN: 145344 Hom.: 0 Cov.: 29 AF XY: 0.0000425 AC XY: 3 AN XY: 70654

African (AFR) AF: 0.0000986 AC: 4 AN: 40564

American (AMR) AF: 0.00 AC: 0 AN: 14674

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3376

East Asian (EAS) AF: 0.00 AC: 0 AN: 4966

South Asian (SAS) AF: 0.00 AC: 0 AN: 4774

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8226

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 308

European-Non Finnish (NFE) AF: 0.0000153 AC: 1 AN: 65548

Other (OTH) AF: 0.00 AC: 0 AN: 2004

Alfa AF: 0.0000712 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 07, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.224C>T (p.A75V) alteration is located in exon 1 (coding exon 1) of the MMP24 gene. This alteration results from a C to T substitution at nucleotide position 224, causing the alanine (A) at amino acid position 75 to be replaced by a valine (V). 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	0.094
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	16
DANN	Benign	0.97
DEOGEN2	Benign	0.087	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.0026	N
LIST_S2	Benign	0.35	T
M_CAP	Benign	0.032	D
MetaRNN	Benign	0.069	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.55	N
PhyloP100		0.057
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-0.62	N
REVEL	Benign	0.0040
Sift	Benign	0.20	T
Sift4G	Uncertain	0.055	T
Polyphen		0.015	B
Vest4		0.058
MutPred		0.38		Gain of helix (P = 0.0078);
MVP		0.48
MPC		0.54
ClinPred		0.077	T
GERP RS		-0.10
PromoterAI		0.016	Neutral
Varity_R		0.047
gMVP		0.28
Mutation Taster		=90/10	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.15		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;