rs1784423

Variant names:

• chr11-102606664-A-G
• rs1784423
• NM_004771.4:c.824T>C

Your query was ambiguous. Multiple possible variants found:

• chr11-102606664-A-G
• chr11-102606664-A-T

Variant summary

Our verdict is Benign. The variant received -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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V275L) has been classified as Uncertain significance.

• 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:4
• Conservation: PhyloP100: 0.748
• Publications: 34 publications found

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]

MMP20 Gene-Disease associations (from GenCC):

• amelogenesis imperfecta hypomaturation type 2A2

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• amelogenesis imperfecta type 2

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 259541.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 rank	MANE	Protein	UniProt
MMP20	NM_004771.4	c.824T>C	p.Val275Ala	missense_variant	Exon 6 of 10	ENST00000260228.3	NP_004762.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MMP20	ENST00000260228.3	c.824T>C	p.Val275Ala	missense_variant	Exon 6 of 10	1	NM_004771.4	ENSP00000260228.2
MMP20	ENST00000544938.1	n.280T>C		non_coding_transcript_exon_variant	Exon 3 of 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

GnomAD2 exomes AF: 0.453 AC: 113885 AN: 251382 AF XY: 0.463

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 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

African (AFR) AF: 0.296 AC: 9893 AN: 33450

American (AMR) AF: 0.462 AC: 20661 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.462 AC: 12056 AN: 26122

East Asian (EAS) AF: 0.436 AC: 17311 AN: 39686

South Asian (SAS) AF: 0.575 AC: 49532 AN: 86214

European-Finnish (FIN) AF: 0.357 AC: 19039 AN: 53400

Middle Eastern (MID) AF: 0.542 AC: 3125 AN: 5764

European-Non Finnish (NFE) AF: 0.459 AC: 509829 AN: 1110218

Other (OTH) AF: 0.457 AC: 27568 AN: 60300

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

African (AFR) AF: 0.308 AC: 12773 AN: 41430

American (AMR) AF: 0.443 AC: 6774 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.450 AC: 1561 AN: 3468

East Asian (EAS) AF: 0.455 AC: 2344 AN: 5156

South Asian (SAS) AF: 0.587 AC: 2829 AN: 4822

European-Finnish (FIN) AF: 0.336 AC: 3552 AN: 10564

Middle Eastern (MID) AF: 0.503 AC: 148 AN: 294

European-Non Finnish (NFE) AF: 0.452 AC: 30712 AN: 67954

Other (OTH) AF: 0.450 AC: 946 AN: 2102

Alfa AF: 0.445 Hom.: 49669

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:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Nov 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Amelogenesis imperfecta hypomaturation type 2A2 Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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
PhyloP100		0.75
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
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: rs1784423; hg19: chr11-102477395; COSMIC: COSV52774315; COSMIC: COSV52774315;