11-102713404-G-A

Variant names:

• chr11-102713404-G-A
• rs35231465
• NM_002424.3:c.1348C>T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BS1 BS2

The NM_002424.3(MMP8):​c.1348C>T​(p.Gln450*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0207 in 1,613,238 control chromosomes in the GnomAD database, including 442 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.015 (38 hom., cov: 33)
  • Exomes 𝑓: 0.021 (404 hom.)
• Consequence: MMP8 NM_002424.3 stop_gained
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.07

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 -8 ACMG points.

• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0154 (2340/152260) while in subpopulation NFE AF= 0.0244 (1662/68010). AF 95% confidence interval is 0.0235. There are 38 homozygotes in gnomad4. There are 1075 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 38 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MMP8	NM_002424.3	c.1348C>T	p.Gln450*	stop_gained	Exon 10 of 10	ENST00000236826.8	NP_002415.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MMP8	ENST00000236826.8	c.1348C>T	p.Gln450*	stop_gained	Exon 10 of 10	1	NM_002424.3	ENSP00000236826.3
MMP8	ENST00000438475	c.*87C>T		3_prime_UTR_variant	Exon 9 of 9	5		ENSP00000401004.2
MMP8	ENST00000528662.6	n.*1325C>T		non_coding_transcript_exon_variant	Exon 12 of 12	5		ENSP00000431431.2
MMP8	ENST00000528662.6	n.*1325C>T		3_prime_UTR_variant	Exon 12 of 12	5		ENSP00000431431.2

Frequencies

GnomAD3 genomes AF: 0.0154 AC: 2340 AN: 152142 Hom.: 38 Cov.: 33

Gnomad AFR AF: 0.00490

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0146

Gnomad ASJ AF: 0.0202

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.0130

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0244

Gnomad OTH AF: 0.0172

GnomAD3 exomes AF: 0.0163 AC: 4086 AN: 250812 Hom.: 58 AF XY: 0.0165 AC XY: 2236 AN XY: 135530

Gnomad AFR exome AF: 0.00394

Gnomad AMR exome AF: 0.0122

Gnomad ASJ exome AF: 0.0196

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000817

Gnomad FIN exome AF: 0.0163

Gnomad NFE exome AF: 0.0256

Gnomad OTH exome AF: 0.0200

GnomAD4 exome AF: 0.0212 AC: 30974 AN: 1460978 Hom.: 404 Cov.: 31 AF XY: 0.0207 AC XY: 15051 AN XY: 726828

Gnomad4 AFR exome AF: 0.00275

Gnomad4 AMR exome AF: 0.0127

Gnomad4 ASJ exome AF: 0.0199

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00129

Gnomad4 FIN exome AF: 0.0174

Gnomad4 NFE exome AF: 0.0248

Gnomad4 OTH exome AF: 0.0185

GnomAD4 genome AF: 0.0154 AC: 2340 AN: 152260 Hom.: 38 Cov.: 33 AF XY: 0.0144 AC XY: 1075 AN XY: 74434

Gnomad4 AFR AF: 0.00488

Gnomad4 AMR AF: 0.0146

Gnomad4 ASJ AF: 0.0202

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.0130

Gnomad4 NFE AF: 0.0244

Gnomad4 OTH AF: 0.0170

Alfa AF: 0.0225 Hom.: 76

Bravo AF: 0.0156

TwinsUK AF: 0.0259 AC: 96

ALSPAC AF: 0.0304 AC: 117

ESP6500AA AF: 0.00454 AC: 20

ESP6500EA AF: 0.0226 AC: 194

ExAC AF: 0.0161 AC: 1950

Asia WGS AF: 0.00289 AC: 10 AN: 3478

EpiCase AF: 0.0251

EpiControl AF: 0.0254

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 in ESP (all): 214/13004= 1.64% -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.32
CADD	Pathogenic	35
DANN	Benign	0.73
Eigen	Benign	-0.84
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.095	N
Vest4		0.67
GERP RS		-2.5

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: rs35231465; hg19: chr11-102584135;