20-35226781-C-T

Position:

• chr20-35226781-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Moderate BP6_Moderate BS1 BS2

The NM_006690.4(MMP24):​c.43C>T​(p.Pro15Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.33 (3 hom., cov: 0)
  • Exomes 𝑓: 0.0016 (2 hom.)
  • Failed GnomAD Quality Control
• Consequence: MMP24 NM_006690.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.238

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 Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.06906623).
• BP6: Variant 20-35226781-C-T is Benign according to our data. Variant chr20-35226781-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 2362130.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4_exome allele frequency = 0.0016 (252/157094) while in subpopulation AFR AF= 0.0174 (229/13176). AF 95% confidence interval is 0.0155. There are 2 homozygotes in gnomad4_exome. There are 108 alleles in male gnomad4_exome subpopulation. Median coverage is 0. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 2 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MMP24	NM_006690.4	c.43C>T	p.Pro15Ser	missense_variant	1/9	ENST00000246186.8
MMP24-AS1-EDEM2	NM_001355008.2	c.-351-8720G>A		intron_variant
MMP24	XM_017027597.2	c.43C>T	p.Pro15Ser	missense_variant	1/8
MMP24	XM_011528500.3	c.43C>T	p.Pro15Ser	missense_variant	1/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MMP24	ENST00000246186.8	c.43C>T	p.Pro15Ser	missense_variant	1/9	1	NM_006690.4	P1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 533 AN: 1594 Hom.: 3 Cov.: 0 FAILED QC

Gnomad AFR AF: 0.407

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.243

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: 0.00758

Gnomad OTH AF: 0.278

GnomAD4 exome AF: 0.00160 AC: 252 AN: 157094 Hom.: 2 Cov.: 0 AF XY: 0.00149 AC XY: 108 AN XY: 72550

Gnomad4 AFR exome AF: 0.0174

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000164

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000771

Gnomad4 OTH exome AF: 0.00378

GnomAD4 genome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.334 AC: 533 AN: 1596 Hom.: 3 Cov.: 0 AF XY: 0.325 AC XY: 257 AN XY: 790

Gnomad4 AFR AF: 0.405

Gnomad4 AMR AF: 0.243

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00758

Gnomad4 OTH AF: 0.278

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 09, 2022

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	0.0047	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	17
DANN	Benign	0.95
DEOGEN2	Benign	0.049	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.0024	N
LIST_S2	Benign	0.29	T
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.069	T
MetaSVM	Benign	-0.85	T
MutationAssessor	Benign	0.0	N
MutationTaster	Benign	1.0	D;N
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	0.29	N
REVEL	Benign	0.28
Sift	Benign	0.29	T
Sift4G	Benign	0.10	T
Polyphen		0.0010	B
Vest4		0.22
MutPred		0.31		Gain of phosphorylation at P15 (P = 0.0013);
MVP		0.47
MPC		0.55
ClinPred		0.093	T
GERP RS		-2.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.039
gMVP		0.27

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

LitVar

Other links and lift over

dbSNP: rs967207850; hg19: chr20-33814584;