Genetic Variant MMP13:c.637+825G>A (chr11-102953331-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_002427.4(MMP13):c.637+825G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.832 in 152,138 control chromosomes in the GnomAD database, including 52,809 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.83 ( 52809 hom., cov: 32)

Consequence

MMP13
NM_002427.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.948

Publications

2 publications found

Variant links:

Genes affected

MMP13 (HGNC:7159): (matrix metallopeptidase 13) 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. This protease cleaves type II collagen more efficiently than types I and III. It may be involved in articular cartilage turnover and cartilage pathophysiology associated with osteoarthritis. Mutations in this gene are associated with metaphyseal anadysplasia. This gene is part of a cluster of MMP genes on chromosome 11. [provided by RefSeq, Jan 2016]

MMP13 Gene-Disease associations (from GenCC):

spondyloepimetaphyseal dysplasia, Missouri type
Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics
metaphyseal chondrodysplasia, Spahr type
Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, G2P, Orphanet, Labcorp Genetics (formerly Invitae)
metaphyseal anadysplasia
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

MMP13 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.9).

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.873 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MMP13	NM_002427.4 link	c.637+825G>A		intron_variant	Intron 4 of 9	ENST00000260302.8	NP_002418.1	P45452Q53H33

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MMP13	ENST00000260302.8 link	c.637+825G>A		intron_variant	Intron 4 of 9	1	NM_002427.4	ENSP00000260302.3		P45452
MMP13	ENST00000340273.4 link	c.637+825G>A		intron_variant	Intron 4 of 10	1		ENSP00000339672.4		G5E971

Frequencies

GnomAD3 genomes

AF:

0.832

AC:

126504

AN:

152020

Hom.:

52782

Cov.:

show subpopulations

Gnomad AFR

AF:

0.803

Gnomad AMI

AF:

0.764

Gnomad AMR

AF:

0.885

Gnomad ASJ

AF:

0.824

Gnomad EAS

AF:

0.766

Gnomad SAS

AF:

0.694

Gnomad FIN

AF:

0.909

Gnomad MID

AF:

0.905

Gnomad NFE

AF:

0.842

Gnomad OTH

AF:

0.833

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.832

AC:

126577

AN:

152138

Hom.:

52809

Cov.:

AF XY:

0.835

AC XY:

62079

AN XY:

74384

show subpopulations

African (AFR)

AF:

0.803

AC:

33313

AN:

41490

American (AMR)

AF:

0.885

AC:

13520

AN:

15270

Ashkenazi Jewish (ASJ)

AF:

0.824

AC:

2857

AN:

3468

East Asian (EAS)

AF:

0.766

AC:

3969

AN:

5180

South Asian (SAS)

AF:

0.693

AC:

3341

AN:

4818

European-Finnish (FIN)

AF:

0.909

AC:

9635

AN:

10600

Middle Eastern (MID)

AF:

0.905

AC:

266

AN:

294

European-Non Finnish (NFE)

AF:

0.842

AC:

57226

AN:

67994

Other (OTH)

AF:

0.830

AC:

1753

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

1093

2186

3278

4371

5464

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

884

1768

2652

3536

4420

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.843

Hom.:

7040

Bravo

AF:

0.830

Asia WGS

AF:

0.730

AC:

2534

AN:

3470

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.90

CADD

Benign

0.50

(source)

DANN

Benign

0.35

PhyloP100

-0.95

Mutation Taster

=100/0

polymorphism (auto)

(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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over