rs1784423

chr11-102606664-A-Gchr11-102606664-A-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004771.4(MMP20):c.824T>C(p.Val275Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.454 in 1,611,858 control chromosomes in the GnomAD database, including 168,714 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 (★★). Synonymous variant affecting the same amino acid position (i.e. V275V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.41 (13093 hom., cov: 32)
  • Exomes 𝑓: 0.46 (155621 hom.)
• Consequence: MMP20 NM_004771.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.748

Genes affected

MMP20 (HGNC:7167): (matrix metallopeptidase 20) Proteins of the matrix metalloproteinase (MMP) 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. Most MMP's are secreted as inactive proproteins which are activated when cleaved by extracellular proteinases. The protein encoded by this gene degrades amelogenin, the major protein component of dental enamel matrix, and thus thought to play a role in tooth enamel formation. A mutation in this gene, which alters the normal splice pattern and results in premature termination of the encoded protein, has been associated with amelogenesis imperfecta. This gene is part of a cluster of MMP genes located on chromosome 11q22.3. [provided by RefSeq, Aug 2011]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.6944017E-5).
• BP6: Variant 11-102606664-A-G is Benign according to our data. Variant chr11-102606664-A-G is described in ClinVar as [Benign]. Clinvar id is 259541.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-102606664-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.569 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MMP20	NM_004771.4	c.824T>C	p.Val275Ala	missense_variant	6/10	ENST00000260228.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MMP20	ENST00000260228.3	c.824T>C	p.Val275Ala	missense_variant	6/10	1	NM_004771.4	P1
MMP20	ENST00000544938.1	n.280T>C		non_coding_transcript_exon_variant	3/5	3

Frequencies

GnomAD3 genomes AF: 0.408 AC: 61992 AN: 151872 Hom.: 13080 Cov.: 32

Gnomad AFR AF: 0.309

Gnomad AMI AF: 0.428

Gnomad AMR AF: 0.443

Gnomad ASJ AF: 0.450

Gnomad EAS AF: 0.455

Gnomad SAS AF: 0.586

Gnomad FIN AF: 0.336

Gnomad MID AF: 0.500

Gnomad NFE AF: 0.452

Gnomad OTH AF: 0.443

GnomAD3 exomes AF: 0.453 AC: 113885 AN: 251382 Hom.: 26455 AF XY: 0.463 AC XY: 62925 AN XY: 135874

Gnomad AFR exome AF: 0.302

Gnomad AMR exome AF: 0.464

Gnomad ASJ exome AF: 0.462

Gnomad EAS exome AF: 0.450

Gnomad SAS exome AF: 0.582

Gnomad FIN exome AF: 0.353

Gnomad NFE exome AF: 0.456

Gnomad OTH exome AF: 0.445

GnomAD4 exome AF: 0.458 AC: 669014 AN: 1459868 Hom.: 155621 Cov.: 48 AF XY: 0.463 AC XY: 335945 AN XY: 726334

Gnomad4 AFR exome AF: 0.296

Gnomad4 AMR exome AF: 0.462

Gnomad4 ASJ exome AF: 0.462

Gnomad4 EAS exome AF: 0.436

Gnomad4 SAS exome AF: 0.575

Gnomad4 FIN exome AF: 0.357

Gnomad4 NFE exome AF: 0.459

Gnomad4 OTH exome AF: 0.457

GnomAD4 genome AF: 0.408 AC: 62029 AN: 151990 Hom.: 13093 Cov.: 32 AF XY: 0.406 AC XY: 30172 AN XY: 74310

Gnomad4 AFR AF: 0.308

Gnomad4 AMR AF: 0.443

Gnomad4 ASJ AF: 0.450

Gnomad4 EAS AF: 0.455

Gnomad4 SAS AF: 0.587

Gnomad4 FIN AF: 0.336

Gnomad4 NFE AF: 0.452

Gnomad4 OTH AF: 0.450

Alfa AF: 0.453 Hom.: 34364

Bravo AF: 0.411

TwinsUK AF: 0.450 AC: 1668

ALSPAC AF: 0.467 AC: 1800

ESP6500AA AF: 0.308 AC: 1359

ESP6500EA AF: 0.457 AC: 3927

ExAC AF: 0.452 AC: 54856

Asia WGS AF: 0.548 AC: 1906 AN: 3478

EpiCase AF: 0.462

EpiControl AF: 0.464

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 12, 2018

- -

Amelogenesis imperfecta hypomaturation type 2A2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.062
BayesDel_addAF	Benign	-0.82	T
BayesDel_noAF	Benign	-0.80
Cadd	Benign	13
Dann	Benign	0.56
DEOGEN2	Benign	0.031	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.0016	N
LIST_S2	Benign	0.017	T
MetaRNN	Benign	0.000017	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	-1.3	N
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.26	T
PROVEAN	Benign	0.36	N
REVEL	Benign	0.096
Sift	Benign	1.0	T
Sift4G	Benign	0.82	T
Polyphen		0.0	B
Vest4		0.011
MPC		0.039
ClinPred		0.0068	T
GERP RS		4.5
Varity_R		0.031
gMVP		0.26

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: rs1784423; hg19: chr11-102477395; COSMIC: COSV52774315; COSMIC: COSV52774315;