Genetic Variant NM_002424.3:c.1379A>C (chr11-102713373-T-G) – ACMG Classification: Benign (-12 pts)

Variant summary

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

The NM_002424.3(MMP8):c.1379A>C(p.Lys460Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0575 in 1,612,716 control chromosomes in the GnomAD database, including 3,936 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.094 ( 1094 hom., cov: 33)

Exomes 𝑓: 0.054 ( 2842 hom. )

Consequence

MMP8
NM_002424.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.322

Publications

33 publications found

Variant links:

Genes affected

MMP8 (HGNC:7175): (matrix metallopeptidase 8) This gene encodes a member of the matrix metalloproteinase (MMP) family of proteins. These proteins are involved in the breakdown of extracellular matrix in embryonic development, reproduction, and tissue remodeling, as well as in disease processes, such as arthritis and metastasis. Proteolysis at different sites on this protein results in multiple active forms of the enzyme with distinct N-termini. This protein functions in the degradation of type I, II and III collagens. The gene is part of a cluster of MMP genes which localize to chromosome 11q22.3. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2015]

MMP8 links:

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ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (MetaRNN=0.0028057992).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.205 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MMP8	NM_002424.3 link	c.1379A>C	p.Lys460Thr	missense_variant	Exon 10 of 10	ENST00000236826.8	NP_002415.1	P22894

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
MMP8	ENST00000236826.8 link	c.1379A>C	p.Lys460Thr	missense_variant	Exon 10 of 10	1	NM_002424.3	ENSP00000236826.3	P22894
MMP8	ENST00000528662.6 link	n.*1356A>C		non_coding_transcript_exon_variant	Exon 12 of 12	5		ENSP00000431431.2	E9PL87
MMP8	ENST00000438475.2 link	c.*118A>C		3_prime_UTR_variant	Exon 9 of 9	5		ENSP00000401004.2	H7C1M3
MMP8	ENST00000528662.6 link	n.*1356A>C		3_prime_UTR_variant	Exon 12 of 12	5		ENSP00000431431.2	E9PL87

Frequencies

GnomAD3 genomes

AF:

0.0943

AC:

14346

AN:

152130

Hom.:

1089

Cov.:

show subpopulations

Gnomad AFR

AF:

0.209

Gnomad AMI

AF:

0.0351

Gnomad AMR

AF:

0.0577

Gnomad ASJ

AF:

0.0637

Gnomad EAS

AF:

0.00885

Gnomad SAS

AF:

0.0577

Gnomad FIN

AF:

0.0520

Gnomad MID

AF:

0.104

Gnomad NFE

AF:

0.0511

Gnomad OTH

AF:

0.0880

GnomAD2 exomes

AF:

0.0604

AC:

15146

AN:

250740

AF XY:

0.0583

show subpopulations

Gnomad AFR exome

AF:

0.206

Gnomad AMR exome

AF:

0.0382

Gnomad ASJ exome

AF:

0.0674

Gnomad EAS exome

AF:

0.00757

Gnomad FIN exome

AF:

0.0517

Gnomad NFE exome

AF:

0.0552

Gnomad OTH exome

AF:

0.0720

GnomAD4 exome

AF:

0.0536

AC:

78330

AN:

1460468

Hom.:

2842

Cov.:

AF XY:

0.0536

AC XY:

38968

AN XY:

726630

show subpopulations

African (AFR)

AF:

0.218

AC:

7269

AN:

33374

American (AMR)

AF:

0.0403

AC:

1801

AN:

44688

Ashkenazi Jewish (ASJ)

AF:

0.0657

AC:

1715

AN:

26110

East Asian (EAS)

AF:

0.00565

AC:

224

AN:

39666

South Asian (SAS)

AF:

0.0604

AC:

5207

AN:

86218

European-Finnish (FIN)

AF:

0.0527

AC:

2811

AN:

53390

Middle Eastern (MID)

AF:

0.110

AC:

631

AN:

5762

European-Non Finnish (NFE)

AF:

0.0494

AC:

54899

AN:

1110932

Other (OTH)

AF:

0.0625

AC:

3773

AN:

60328

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

3359

6717

10076

13434

16793

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2078

4156

6234

8312

10390

<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:

0.0944

AC:

14377

AN:

152248

Hom.:

1094

Cov.:

AF XY:

0.0933

AC XY:

6947

AN XY:

74432

show subpopulations

African (AFR)

AF:

0.209

AC:

8673

AN:

41520

American (AMR)

AF:

0.0576

AC:

881

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.0637

AC:

221

AN:

3470

East Asian (EAS)

AF:

0.00887

AC:

AN:

5188

South Asian (SAS)

AF:

0.0580

AC:

280

AN:

4830

European-Finnish (FIN)

AF:

0.0520

AC:

552

AN:

10622

Middle Eastern (MID)

AF:

0.112

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0511

AC:

3475

AN:

68014

Other (OTH)

AF:

0.0870

AC:

184

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

639

1277

1916

2554

3193

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

156

312

468

624

780

<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:

0.0645

Hom.:

1604

Bravo

AF:

0.0994

TwinsUK

AF:

0.0464

AC:

172

ALSPAC

AF:

0.0444

AC:

171

ESP6500AA

AF:

0.200

AC:

879

ESP6500EA

AF:

0.0536

AC:

461

ExAC

AF:

0.0661

AC:

8026

Asia WGS

AF:

0.0450

AC:

158

AN:

3478

EpiCase

AF:

0.0587

EpiControl

AF:

0.0599

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.83

BayesDel_noAF

Benign

-0.82

CADD

Benign

4.6

(source)

DANN

Benign

0.87

DEOGEN2

Benign

0.055

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.037

LIST_S2

Benign

0.19

MetaRNN

Benign

0.0028

MetaSVM

Benign

-0.92

MutationAssessor

Benign

0.035

PhyloP100

-0.32

PrimateAI

Benign

0.29

PROVEAN

Benign

0.020

REVEL

Benign

0.012

Sift

Benign

0.16

Sift4G

Benign

0.21

Polyphen

0.0020

Vest4

0.086

MPC

0.045

ClinPred

0.0028

GERP RS

-8.0

Varity_R

0.045

gMVP

0.45

Mutation Taster

=99/1

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over