Genetic Variant NM_002424.3:c.1387A>G (chr11-102713365-T-C) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_002424.3(MMP8):c.1387A>G(p.Asn463Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00121 in 1,612,686 control chromosomes in the GnomAD database, including 21 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0065 ( 13 hom., cov: 33)

Exomes 𝑓: 0.00066 ( 8 hom. )

Consequence

MMP8
NM_002424.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 1.34

Publications

4 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.011686385).

BP6

Variant 11-102713365-T-C is Benign according to our data. Variant chr11-102713365-T-C is described in ClinVar as Benign. ClinVar VariationId is 714053.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00647 (985/152336) while in subpopulation AFR AF = 0.0226 (941/41586). AF 95% confidence interval is 0.0214. There are 13 homozygotes in GnomAd4. There are 459 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 13 gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002424.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MMP8	NM_002424.3	MANE Select	c.1387A>G	p.Asn463Asp	missense	Exon 10 of 10	NP_002415.1	P22894
MMP8	NM_001304441.2		c.1318A>G	p.Asn440Asp	missense	Exon 11 of 11	NP_001291370.1
MMP8	NM_001304442.2		c.1318A>G	p.Asn440Asp	missense	Exon 11 of 11	NP_001291371.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MMP8	ENST00000236826.8	TSL:1 MANE Select	c.1387A>G	p.Asn463Asp	missense	Exon 10 of 10	ENSP00000236826.3	P22894
MMP8	ENST00000438475.2	TSL:5	c.*126A>G		3_prime_UTR	Exon 9 of 9	ENSP00000401004.2	H7C1M3
MMP8	ENST00000528662.6	TSL:5	n.*1364A>G		non_coding_transcript_exon	Exon 12 of 12	ENSP00000431431.2	E9PL87

Frequencies

GnomAD3 genomes

AF:

0.00646

AC:

983

AN:

152218

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0226

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00190

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:

0.000132

Gnomad OTH

AF:

0.00287

GnomAD2 exomes

AF:

0.00174

AC:

435

AN:

250688

AF XY:

0.00117

show subpopulations

Gnomad AFR exome

AF:

0.0235

Gnomad AMR exome

AF:

0.00125

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000707

Gnomad OTH exome

AF:

0.000327

GnomAD4 exome

AF:

0.000659

AC:

962

AN:

1460350

Hom.:

Cov.:

AF XY:

0.000570

AC XY:

414

AN XY:

726560

show subpopulations

African (AFR)

AF:

0.0229

AC:

765

AN:

33392

American (AMR)

AF:

0.00157

AC:

AN:

44678

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26104

East Asian (EAS)

AF:

0.00

AC:

AN:

39662

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86232

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53382

Middle Eastern (MID)

AF:

0.00104

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.0000189

AC:

AN:

1110828

Other (OTH)

AF:

0.00164

AC:

AN:

60308

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

134

178

223

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

104

130

<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:

0.00647

AC:

985

AN:

152336

Hom.:

Cov.:

AF XY:

0.00616

AC XY:

459

AN XY:

74480

show subpopulations

African (AFR)

AF:

0.0226

AC:

941

AN:

41586

American (AMR)

AF:

0.00190

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000132

AC:

AN:

68030

Other (OTH)

AF:

0.00284

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

102

153

204

255

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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:

0.00282

Hom.:

Bravo

AF:

0.00739

ESP6500AA

AF:

0.0209

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00213

AC:

258

Asia WGS

AF:

0.00260

AC:

AN:

3478

EpiCase

AF:

0.0000546

EpiControl

AF:

0.00

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.63

BayesDel_noAF

Benign

-0.66

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.25

Eigen

Benign

-0.33

Eigen_PC

Benign

-0.23

FATHMM_MKL

Uncertain

0.81

LIST_S2

Benign

0.37

MetaRNN

Benign

0.012

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.4

PhyloP100

1.3

PrimateAI

Uncertain

0.54

PROVEAN

Uncertain

-2.8

REVEL

Benign

0.074

Sift

Benign

0.11

Sift4G

Benign

0.33

Polyphen

0.014

Vest4

0.39

MVP

0.43

MPC

0.29

ClinPred

0.017

GERP RS

4.5

Varity_R

0.18

gMVP

0.43

Mutation Taster

=94/6

polymorphism

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over