Genetic Variant MMP12:c.-124A>G (chr11-102875061-T-C) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_ModerateBA1

The NM_002426.6(MMP12):c.-124A>G variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.108 in 600,826 control chromosomes in the GnomAD database, including 4,255 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 0.092 ( 921 hom., cov: 33)

Exomes 𝑓: 0.11 ( 3334 hom. )

Consequence

MMP12
NM_002426.6 upstream_gene

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.0820

Publications

169 publications found

Variant links:

Genes affected

MMP12 (HGNC:7158): (matrix metallopeptidase 12) 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 degrades soluble and insoluble elastin. This gene may play a role in aneurysm formation and mutations in this gene are associated with lung function and chronic obstructive pulmonary disease (COPD). This gene is part of a cluster of MMP genes on chromosome 11. [provided by RefSeq, Jan 2016]

MMP12 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.42).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.126 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002426.6. 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
	MMP12	NM_002426.6	MANE Select	c.-124A>G		upstream_gene	N/A	NP_002417.2	P39900

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MMP12	ENST00000571244.3	TSL:1 MANE Select	c.-124A>G		upstream_gene	N/A	ENSP00000458585.1	P39900

Frequencies

GnomAD3 genomes

AF:

0.0922

AC:

14026

AN:

152134

Hom.:

920

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0225

Gnomad AMI

AF:

0.107

Gnomad AMR

AF:

0.0700

Gnomad ASJ

AF:

0.104

Gnomad EAS

AF:

0.0237

Gnomad SAS

AF:

0.0670

Gnomad FIN

AF:

0.204

Gnomad MID

AF:

0.127

Gnomad NFE

AF:

0.128

Gnomad OTH

AF:

0.0908

GnomAD4 exome

AF:

0.114

AC:

50958

AN:

448574

Hom.:

3334

Cov.:

AF XY:

0.112

AC XY:

26458

AN XY:

235810

show subpopulations

African (AFR)

AF:

0.0223

AC:

279

AN:

12522

American (AMR)

AF:

0.0625

AC:

1186

AN:

18986

Ashkenazi Jewish (ASJ)

AF:

0.115

AC:

1595

AN:

13862

East Asian (EAS)

AF:

0.0223

AC:

679

AN:

30462

South Asian (SAS)

AF:

0.0802

AC:

3178

AN:

39632

European-Finnish (FIN)

AF:

0.179

AC:

6003

AN:

33446

Middle Eastern (MID)

AF:

0.123

AC:

288

AN:

2346

European-Non Finnish (NFE)

AF:

0.129

AC:

34958

AN:

271866

Other (OTH)

AF:

0.110

AC:

2792

AN:

25452

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

2049

4097

6146

8194

10243

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

238

476

714

952

1190

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0921

AC:

14027

AN:

152252

Hom.:

921

Cov.:

AF XY:

0.0935

AC XY:

6961

AN XY:

74432

show subpopulations

African (AFR)

AF:

0.0224

AC:

931

AN:

41570

American (AMR)

AF:

0.0700

AC:

1070

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.104

AC:

360

AN:

3472

East Asian (EAS)

AF:

0.0238

AC:

123

AN:

5178

South Asian (SAS)

AF:

0.0676

AC:

326

AN:

4820

European-Finnish (FIN)

AF:

0.204

AC:

2156

AN:

10586

Middle Eastern (MID)

AF:

0.133

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.128

AC:

8737

AN:

68016

Other (OTH)

AF:

0.0889

AC:

188

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

659

1318

1978

2637

3296

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

160

320

480

640

800

<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:

0.0561

Hom.:

113

Bravo

AF:

0.0790

Asia WGS

AF:

0.0490

AC:

170

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.42

CADD

Benign

(source)

DANN

Benign

0.71

PhyloP100

-0.082

PromoterAI

-0.088

Neutral

(source)

Splicing

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over