rs652438

chr11-102865911-T-Cchr11-102865911-T-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002426.6(MMP12):c.1070A>G(p.Asn357Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0603 in 1,611,248 control chromosomes in the GnomAD database, including 4,093 homozygotes. In-silico tool predicts a benign outcome for this variant. 9/13 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.097 (989 hom., cov: 32)
  • Exomes 𝑓: 0.057 (3104 hom.)
• Consequence: MMP12 NM_002426.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.62

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]

LOC124902741 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0015932322).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.185 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MMP12	NM_002426.6	c.1070A>G	p.Asn357Ser	missense_variant	8/10	ENST00000571244.3
LOC124902741	XR_007062868.1	n.2705T>C		non_coding_transcript_exon_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MMP12	ENST00000571244.3	c.1070A>G	p.Asn357Ser	missense_variant	8/10	1	NM_002426.6	P1

Frequencies

GnomAD3 genomes AF: 0.0971 AC: 14763 AN: 152092 Hom.: 985 Cov.: 32

Gnomad AFR AF: 0.189

Gnomad AMI AF: 0.116

Gnomad AMR AF: 0.0696

Gnomad ASJ AF: 0.127

Gnomad EAS AF: 0.110

Gnomad SAS AF: 0.0996

Gnomad FIN AF: 0.0406

Gnomad MID AF: 0.161

Gnomad NFE AF: 0.0527

Gnomad OTH AF: 0.0977

GnomAD3 exomes AF: 0.0707 AC: 17522 AN: 247904 Hom.: 878 AF XY: 0.0707 AC XY: 9503 AN XY: 134498

Gnomad AFR exome AF: 0.192

Gnomad AMR exome AF: 0.0411

Gnomad ASJ exome AF: 0.116

Gnomad EAS exome AF: 0.126

Gnomad SAS exome AF: 0.0940

Gnomad FIN exome AF: 0.0403

Gnomad NFE exome AF: 0.0495

Gnomad OTH exome AF: 0.0740

GnomAD4 exome AF: 0.0565 AC: 82460 AN: 1459038 Hom.: 3104 Cov.: 30 AF XY: 0.0579 AC XY: 42014 AN XY: 725876

Gnomad4 AFR exome AF: 0.195

Gnomad4 AMR exome AF: 0.0436

Gnomad4 ASJ exome AF: 0.118

Gnomad4 EAS exome AF: 0.0843

Gnomad4 SAS exome AF: 0.0936

Gnomad4 FIN exome AF: 0.0420

Gnomad4 NFE exome AF: 0.0469

Gnomad4 OTH exome AF: 0.0750

GnomAD4 genome AF: 0.0970 AC: 14769 AN: 152210 Hom.: 989 Cov.: 32 AF XY: 0.0955 AC XY: 7109 AN XY: 74430

Gnomad4 AFR AF: 0.189

Gnomad4 AMR AF: 0.0694

Gnomad4 ASJ AF: 0.127

Gnomad4 EAS AF: 0.110

Gnomad4 SAS AF: 0.0985

Gnomad4 FIN AF: 0.0406

Gnomad4 NFE AF: 0.0527

Gnomad4 OTH AF: 0.102

Alfa AF: 0.0608 Hom.: 666

Bravo AF: 0.103

TwinsUK AF: 0.0445 AC: 165

ALSPAC AF: 0.0464 AC: 179

ESP6500AA AF: 0.181 AC: 648

ESP6500EA AF: 0.0540 AC: 438

ExAC AF: 0.0725 AC: 8759

Asia WGS AF: 0.112 AC: 389 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.43
Cadd	Benign	17
Dann	Benign	0.68
DEOGEN2	Benign	0.081	T
FATHMM_MKL	Benign	0.067	N
LIST_S2	Benign	0.50	T
MetaRNN	Benign	0.0016	T
MutationAssessor	Benign	1.5	L
PrimateAI	Benign	0.28	T
Sift4G	Uncertain	0.0050	D
Polyphen		0.20	B
Vest4		0.15
GERP RS		3.2
Varity_R		0.17
gMVP		0.43

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: rs652438; hg19: chr11-102736642; COSMIC: COSV58259288;