rs3765620

Positions:

• chr11-102724761-G-A
• chr11-102724761-G-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_002424.3(MMP8):​c.95C>T​(p.Thr32Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.57 in 1,586,530 control chromosomes in the GnomAD database, including 261,255 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.63 (30389 hom., cov: 33)
  • Exomes 𝑓: 0.56 (230866 hom.)
• Consequence: MMP8 NM_002424.3 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.684

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=4.8309057E-6).
• BP6: Variant 11-102724761-G-A is Benign according to our data. Variant chr11-102724761-G-A is described in ClinVar as [Benign]. Clinvar id is 403100.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.749 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MMP8	NM_002424.3	c.95C>T	p.Thr32Ile	missense_variant	1/10	ENST00000236826.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MMP8	ENST00000236826.8	c.95C>T	p.Thr32Ile	missense_variant	1/10	1	NM_002424.3	P1

Frequencies

GnomAD3 genomes AF: 0.626 AC: 95189 AN: 151996 Hom.: 30368 Cov.: 33

Gnomad AFR AF: 0.756

Gnomad AMI AF: 0.591

Gnomad AMR AF: 0.587

Gnomad ASJ AF: 0.607

Gnomad EAS AF: 0.633

Gnomad SAS AF: 0.631

Gnomad FIN AF: 0.610

Gnomad MID AF: 0.742

Gnomad NFE AF: 0.558

Gnomad OTH AF: 0.635

GnomAD3 exomes AF: 0.592 AC: 144728 AN: 244278 Hom.: 43548 AF XY: 0.591 AC XY: 78046 AN XY: 132118

Gnomad AFR exome AF: 0.761

Gnomad AMR exome AF: 0.551

Gnomad ASJ exome AF: 0.613

Gnomad EAS exome AF: 0.636

Gnomad SAS exome AF: 0.611

Gnomad FIN exome AF: 0.598

Gnomad NFE exome AF: 0.565

Gnomad OTH exome AF: 0.605

GnomAD4 exome AF: 0.564 AC: 809126 AN: 1434416 Hom.: 230866 Cov.: 31 AF XY: 0.565 AC XY: 402936 AN XY: 712980

Gnomad4 AFR exome AF: 0.765

Gnomad4 AMR exome AF: 0.553

Gnomad4 ASJ exome AF: 0.619

Gnomad4 EAS exome AF: 0.680

Gnomad4 SAS exome AF: 0.611

Gnomad4 FIN exome AF: 0.591

Gnomad4 NFE exome AF: 0.546

Gnomad4 OTH exome AF: 0.586

GnomAD4 genome AF: 0.626 AC: 95245 AN: 152114 Hom.: 30389 Cov.: 33 AF XY: 0.628 AC XY: 46710 AN XY: 74378

Gnomad4 AFR AF: 0.756

Gnomad4 AMR AF: 0.586

Gnomad4 ASJ AF: 0.607

Gnomad4 EAS AF: 0.634

Gnomad4 SAS AF: 0.629

Gnomad4 FIN AF: 0.610

Gnomad4 NFE AF: 0.558

Gnomad4 OTH AF: 0.636

Alfa AF: 0.577 Hom.: 62793

Bravo AF: 0.629

TwinsUK AF: 0.529 AC: 1961

ALSPAC AF: 0.554 AC: 2136

ESP6500AA AF: 0.751 AC: 3309

ESP6500EA AF: 0.557 AC: 4788

ExAC AF: 0.597 AC: 72457

Asia WGS AF: 0.662 AC: 2299 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 28, 2016

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.062
BayesDel_addAF	Benign	-0.69	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	4.0
DANN	Benign	0.95
DEOGEN2	Benign	0.028	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.00022	N
LIST_S2	Benign	0.0083	T
MetaRNN	Benign	0.0000048	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	-1.1	N
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.36	T
PROVEAN	Benign	2.3	N
REVEL	Benign	0.052
Sift	Benign	0.27	T
Sift4G	Benign	0.42	T
Polyphen		0.0	B
Vest4		0.022
MPC		0.041
ClinPred		0.0031	T
GERP RS		0.96
Varity_R		0.037
gMVP		0.18

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: rs3765620; hg19: chr11-102595492; COSMIC: COSV99030574;