Variant rs1056784 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_002429.6(MMP19):c.733C>T(p.Pro245Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0128 in 1,612,574 control chromosomes in the GnomAD database, including 183 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 0.010 ( 20 hom., cov: 31)

Exomes 𝑓: 0.013 ( 163 hom. )

Consequence

MMP19
NM_002429.6 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.381

Variant links:

Genes affected

MMP19 (HGNC:7165): (matrix metallopeptidase 19) This gene encodes a member of a family of proteins that 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 protein is secreted as an inactive proprotein, which is activated upon cleavage by extracellular proteases. Alternative splicing results in multiple transcript variants for this gene. [provided by RefSeq, Jan 2013]

MMP19 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008432239).

BP6

Variant 12-55839529-G-A is Benign according to our data. Variant chr12-55839529-G-A is described in ClinVar as [Benign]. Clinvar id is 773547.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.0102 (1547/152316) while in subpopulation AMR AF= 0.0265 (406/15310). AF 95% confidence interval is 0.0244. There are 20 homozygotes in gnomad4. There are 763 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High AC in GnomAd4 at 1547 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MMP19	NM_002429.6 linkuse as main transcript	c.733C>T	p.Pro245Ser	missense_variant	5/9	ENST00000322569.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MMP19	ENST00000322569.9 linkuse as main transcript	c.733C>T	p.Pro245Ser	missense_variant	5/9	1	NM_002429.6	P1	Q99542-1

Frequencies

GnomAD3 genomes

AF:

0.0102

AC:

1548

AN:

152198

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00273

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0266

Gnomad ASJ

AF:

0.0158

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00537

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0130

Gnomad OTH

AF:

0.0158

GnomAD3 exomes

AF:

0.00883

AC:

2194

AN:

248568

Hom.:

AF XY:

0.00857

AC XY:

1153

AN XY:

134576

show subpopulations

Gnomad AFR exome

AF:

0.00172

Gnomad AMR exome

AF:

0.0151

Gnomad ASJ exome

AF:

0.0161

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000294

Gnomad FIN exome

AF:

0.00384

Gnomad NFE exome

AF:

0.0117

Gnomad OTH exome

AF:

0.0142

GnomAD4 exome

AF:

0.0131

AC:

19100

AN:

1460258

Hom.:

163

Cov.:

AF XY:

0.0125

AC XY:

9095

AN XY:

726028

show subpopulations

Gnomad4 AFR exome

AF:

0.00215

Gnomad4 AMR exome

AF:

0.0165

Gnomad4 ASJ exome

AF:

0.0150

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.000429

Gnomad4 FIN exome

AF:

0.00371

Gnomad4 NFE exome

AF:

0.0152

Gnomad4 OTH exome

AF:

0.0131

GnomAD4 genome

AF:

0.0102

AC:

1547

AN:

152316

Hom.:

Cov.:

AF XY:

0.0102

AC XY:

763

AN XY:

74474

show subpopulations

Gnomad4 AFR

AF:

0.00272

Gnomad4 AMR

AF:

0.0265

Gnomad4 ASJ

AF:

0.0158

Gnomad4 EAS

AF:

0.000194

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00537

Gnomad4 NFE

AF:

0.0130

Gnomad4 OTH

AF:

0.0156

Alfa

AF:

0.0135

Hom.:

Bravo

AF:

0.0120

TwinsUK

AF:

0.0143

AC:

ALSPAC

AF:

0.0158

AC:

ESP6500AA

AF:

0.00272

AC:

ESP6500EA

AF:

0.0107

AC:

ExAC

AF:

0.00771

AC:

936

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.0111

EpiControl

AF:

0.0135

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

- -

MMP19-related disorder

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 04, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.095

BayesDel_addAF

Benign

-0.58

BayesDel_noAF

Benign

-0.59

CADD

Benign

DANN

Benign

0.49

DEOGEN2

Benign

0.028

T;.

Eigen

Benign

-0.67

Eigen_PC

Benign

-0.58

FATHMM_MKL

Benign

0.11

LIST_S2

Benign

0.44

T;T

MetaRNN

Benign

0.0084

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.64

N;.

MutationTaster

Benign

0.72

D;N;N

PrimateAI

Benign

0.28

PROVEAN

Benign

-0.53

N;N

REVEL

Benign

0.050

Sift

Benign

0.90

T;T

Sift4G

Benign

0.72

T;T

Polyphen

0.0070

B;.

Vest4

0.11

MVP

0.45

MPC

0.11

ClinPred

0.0031

GERP RS

3.9

Varity_R

0.065

gMVP

0.28

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over