Genetic Variant NM_002429.6:c.993G>T (chr12-55837910-C-A) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_002429.6(MMP19):c.993G>T(p.Glu331Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000411 in 1,461,052 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. E331E) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

MMP19
NM_002429.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.705

Publications

0 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:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.16677043).

BS2

High AC in GnomAdExome4 at 6 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.993G>T	p.Glu331Asp	missense	Exon 7 of 9	NP_002420.1	Q99542-1
MMP19	NM_001414375.1		c.747G>T	p.Glu249Asp	missense	Exon 6 of 8	NP_001401304.1
MMP19	NM_001272101.2		c.853G>T	p.Gly285Trp	missense	Exon 6 of 7	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.993G>T	p.Glu331Asp	missense	Exon 7 of 9	ENSP00000313437.4	Q99542-1
MMP19	ENST00000552872.5	TSL:1	n.*878G>T		non_coding_transcript_exon	Exon 7 of 9	ENSP00000446776.1	Q99542-4
MMP19	ENST00000552872.5	TSL:1	n.*878G>T		3_prime_UTR	Exon 7 of 9	ENSP00000446776.1	Q99542-4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000411

AC:

AN:

1461052

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726608

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33474

American (AMR)

AF:

0.00

AC:

AN:

44696

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39646

South Asian (SAS)

AF:

0.00

AC:

AN:

86226

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53406

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000540

AC:

AN:

1111350

Other (OTH)

AF:

0.00

AC:

AN:

60352

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.63

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.093

Eigen

Benign

-0.39

Eigen_PC

Benign

-0.35

FATHMM_MKL

Benign

0.42

LIST_S2

Benign

0.82

M_CAP

Benign

0.016

MetaRNN

Benign

0.17

MetaSVM

Benign

-0.95

PhyloP100

-0.70

PrimateAI

Benign

0.35

PROVEAN

Benign

-0.86

REVEL

Benign

0.030

Sift

Benign

0.15

Sift4G

Benign

0.24

Polyphen

0.037

Vest4

0.33

MutPred

0.43

Gain of catalytic residue at G332 (P = 0)

MVP

0.48

MPC

0.10

ClinPred

0.66

GERP RS

-1.2

Varity_R

0.10

gMVP

0.55

Mutation Taster

=92/8

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over