NM_002427.4:c.512-81A>C

Variant names:

• chr11-102954362-T-G
• rs640198
• NM_002427.4:c.512-81A>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002427.4(MMP13):​c.512-81A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.669 in 1,600,998 control chromosomes in the GnomAD database, including 359,870 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.67 (34655 hom., cov: 33)
  • Exomes 𝑓: 0.67 (325215 hom.)
• Consequence: MMP13 NM_002427.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.42
• Publications: 23 publications found

Genes affected

MMP13 (HGNC:7159): (matrix metallopeptidase 13) 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 cleaves type II collagen more efficiently than types I and III. It may be involved in articular cartilage turnover and cartilage pathophysiology associated with osteoarthritis. Mutations in this gene are associated with metaphyseal anadysplasia. This gene is part of a cluster of MMP genes on chromosome 11. [provided by RefSeq, Jan 2016]

MMP13 Gene-Disease associations (from GenCC):

• spondyloepimetaphyseal dysplasia, Missouri type

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics
• metaphyseal chondrodysplasia, Spahr type

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, G2P, Orphanet, Labcorp Genetics (formerly Invitae)
• metaphyseal anadysplasia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 11-102954362-T-G is Benign according to our data. Variant chr11-102954362-T-G is described in ClinVar as Benign. ClinVar VariationId is 1277474.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.716 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MMP13	NM_002427.4	c.512-81A>C		intron_variant	Intron 3 of 9	ENST00000260302.8	NP_002418.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MMP13	ENST00000260302.8	c.512-81A>C		intron_variant	Intron 3 of 9	1	NM_002427.4	ENSP00000260302.3
MMP13	ENST00000340273.4	c.512-81A>C		intron_variant	Intron 3 of 10	1		ENSP00000339672.4

Frequencies

GnomAD3 genomes AF: 0.672 AC: 102183 AN: 151966 Hom.: 34631 Cov.: 33

Gnomad AFR AF: 0.723

Gnomad AMI AF: 0.688

Gnomad AMR AF: 0.653

Gnomad ASJ AF: 0.591

Gnomad EAS AF: 0.468

Gnomad SAS AF: 0.595

Gnomad FIN AF: 0.604

Gnomad MID AF: 0.585

Gnomad NFE AF: 0.682

Gnomad OTH AF: 0.663

GnomAD4 exome AF: 0.668 AC: 968042 AN: 1448914 Hom.: 325215 Cov.: 29 AF XY: 0.665 AC XY: 479387 AN XY: 721126

African (AFR) AF: 0.731 AC: 24234 AN: 33134

American (AMR) AF: 0.656 AC: 28933 AN: 44108

Ashkenazi Jewish (ASJ) AF: 0.583 AC: 15170 AN: 26000

East Asian (EAS) AF: 0.469 AC: 18573 AN: 39564

South Asian (SAS) AF: 0.592 AC: 50663 AN: 85544

European-Finnish (FIN) AF: 0.625 AC: 33224 AN: 53142

Middle Eastern (MID) AF: 0.594 AC: 3404 AN: 5728

European-Non Finnish (NFE) AF: 0.685 AC: 754734 AN: 1101720

Other (OTH) AF: 0.652 AC: 39107 AN: 59974

GnomAD4 genome AF: 0.672 AC: 102265 AN: 152084 Hom.: 34655 Cov.: 33 AF XY: 0.664 AC XY: 49322 AN XY: 74310

African (AFR) AF: 0.723 AC: 30004 AN: 41508

American (AMR) AF: 0.653 AC: 9962 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.591 AC: 2052 AN: 3472

East Asian (EAS) AF: 0.468 AC: 2422 AN: 5174

South Asian (SAS) AF: 0.595 AC: 2867 AN: 4822

European-Finnish (FIN) AF: 0.604 AC: 6386 AN: 10568

Middle Eastern (MID) AF: 0.595 AC: 175 AN: 294

European-Non Finnish (NFE) AF: 0.682 AC: 46380 AN: 67976

Other (OTH) AF: 0.660 AC: 1392 AN: 2108

Alfa AF: 0.677 Hom.: 131909

Bravo AF: 0.677

Asia WGS AF: 0.548 AC: 1909 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Apr 12, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.20
DANN	Benign	0.64
PhyloP100		-1.4
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs640198; hg19: chr11-102825091; COSMIC: COSV107281016;