dbSNP rs1056784: MMP19:p.Pro245Ser (chr12-55839529-G-A) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

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:3

Conservation

PhyloP100: 0.381

Publications

17 publications found

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 Gene-Disease associations (from GenCC):

familial cavitary optic disk anomaly
Inheritance: Unknown, AD Classification: SUPPORTIVE, LIMITED Submitted by: Laboratory for Molecular Medicine, Orphanet

MMP19 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId 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 the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High AC in GnomAd4 at 1547 Unknown,AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002429.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MMP19	NM_002429.6	MANE Select	c.733C>T	p.Pro245Ser	missense	Exon 5 of 9	NP_002420.1	Q99542-1
MMP19	NM_001414375.1		c.521-795C>T		intron	N/A	NP_001401304.1
MMP19	NM_001272101.2		c.521-795C>T		intron	N/A	NP_001259030.1	Q99542-5

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MMP19	ENST00000322569.9	TSL:1 MANE Select	c.733C>T	p.Pro245Ser	missense	Exon 5 of 9	ENSP00000313437.4	Q99542-1
MMP19	ENST00000552872.5	TSL:1	n.*512C>T		non_coding_transcript_exon	Exon 5 of 9	ENSP00000446776.1	Q99542-4
MMP19	ENST00000552872.5	TSL:1	n.*512C>T		3_prime_UTR	Exon 5 of 9	ENSP00000446776.1	Q99542-4

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

GnomAD2 exomes

AF:

0.00883

AC:

2194

AN:

248568

AF XY:

0.00857

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 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

African (AFR)

AF:

0.00215

AC:

AN:

33454

American (AMR)

AF:

0.0165

AC:

737

AN:

44682

Ashkenazi Jewish (ASJ)

AF:

0.0150

AC:

391

AN:

26112

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39624

South Asian (SAS)

AF:

0.000429

AC:

AN:

86222

European-Finnish (FIN)

AF:

0.00371

AC:

198

AN:

53398

Middle Eastern (MID)

AF:

0.00399

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.0152

AC:

16852

AN:

1110678

Other (OTH)

AF:

0.0131

AC:

789

AN:

60324

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

Heterozygous variant carriers

1022

2044

3065

4087

5109

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

676

1352

2028

2704

3380

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0102

AC:

1547

AN:

152316

Hom.:

Cov.:

AF XY:

0.0102

AC XY:

763

AN XY:

74474

show subpopulations

African (AFR)

AF:

0.00272

AC:

113

AN:

41566

American (AMR)

AF:

0.0265

AC:

406

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.0158

AC:

AN:

3472

East Asian (EAS)

AF:

0.000194

AC:

AN:

5166

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00537

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0130

AC:

882

AN:

68032

Other (OTH)

AF:

0.0156

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

147

220

294

367

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0125

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

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

MMP19-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.095

BayesDel_addAF

Benign

-0.58

BayesDel_noAF

Benign

-0.59

CADD

Benign

(source)

DANN

Benign

0.49

DEOGEN2

Benign

0.028

Eigen

Benign

-0.67

Eigen_PC

Benign

-0.58

FATHMM_MKL

Benign

0.11

LIST_S2

Benign

0.44

MetaRNN

Benign

0.0084

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.64

PhyloP100

0.38

PrimateAI

Benign

0.28

PROVEAN

Benign

-0.53

REVEL

Benign

0.050

Sift

Benign

0.90

Sift4G

Benign

0.72

Polyphen

0.0070

Vest4

0.11

MVP

0.45

MPC

0.11

ClinPred

0.0031

GERP RS

3.9

Varity_R

0.065

gMVP

0.28

Mutation Taster

=97/3

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over