11-102790512-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_002421.4(MMP1):ā€‹c.1310A>Gā€‹(p.Tyr437Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000631 in 1,585,686 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: š‘“ 0.000013 ( 0 hom., cov: 33)
Exomes š‘“: 0.0000056 ( 0 hom. )

Consequence

MMP1
NM_002421.4 missense

Scores

6
6
7

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.08
Variant links:
Genes affected
MMP1 (HGNC:7155): (matrix metallopeptidase 1) This gene encodes a member of the peptidase M10 family of matrix metalloproteinases (MMPs). Proteins in this 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. The encoded preproprotein is proteolytically processed to generate the mature protease. This secreted protease breaks down the interstitial collagens, including types I, II, and III. The gene is part of a cluster of MMP genes on chromosome 11. Mutations in this gene are associated with chronic obstructive pulmonary disease (COPD). Alternative splicing results in multiple transcript variants, at least one of which encodes an isoform that is proteolytically processed. [provided by RefSeq, Jan 2016]
WTAPP1 (HGNC:44115): (WTAP pseudogene 1)

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.946

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
MMP1NM_002421.4 linkc.1310A>G p.Tyr437Cys missense_variant 10/10 ENST00000315274.7 NP_002412.1 P03956Q53G95
MMP1NM_001145938.2 linkc.1112A>G p.Tyr371Cys missense_variant 10/10 NP_001139410.1 B4DN15
WTAPP1NR_038390.1 linkn.390-2633T>C intron_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
MMP1ENST00000315274.7 linkc.1310A>G p.Tyr437Cys missense_variant 10/101 NM_002421.4 ENSP00000322788.6 P03956

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152166
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000655
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000426
AC:
1
AN:
234816
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
126780
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000316
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000558
AC:
8
AN:
1433520
Hom.:
0
Cov.:
28
AF XY:
0.00000420
AC XY:
3
AN XY:
713872
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000238
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000366
Gnomad4 OTH exome
AF:
0.0000506
GnomAD4 genome
AF:
0.0000131
AC:
2
AN:
152166
Hom.:
0
Cov.:
33
AF XY:
0.0000269
AC XY:
2
AN XY:
74342
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.0000655
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000302
ExAC
AF:
0.00000824
AC:
1

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsJul 10, 2024The c.1310A>G (p.Y437C) alteration is located in exon 10 (coding exon 10) of the MMP1 gene. This alteration results from a A to G substitution at nucleotide position 1310, causing the tyrosine (Y) at amino acid position 437 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.26
BayesDel_addAF
Uncertain
0.095
D
BayesDel_noAF
Benign
-0.10
CADD
Pathogenic
26
DANN
Uncertain
1.0
DEOGEN2
Benign
0.30
T
Eigen
Pathogenic
0.88
Eigen_PC
Pathogenic
0.83
FATHMM_MKL
Uncertain
0.91
D
LIST_S2
Uncertain
0.96
D
M_CAP
Benign
0.040
D
MetaRNN
Pathogenic
0.95
D
MetaSVM
Benign
-0.88
T
MutationAssessor
Pathogenic
3.7
H
PrimateAI
Benign
0.46
T
PROVEAN
Pathogenic
-6.5
D
REVEL
Uncertain
0.37
Sift
Uncertain
0.0010
D
Sift4G
Pathogenic
0.0010
D
Polyphen
1.0
D
Vest4
0.74
MutPred
0.80
Loss of sheet (P = 0.0817);
MVP
0.75
MPC
0.039
ClinPred
1.0
D
GERP RS
6.2
Varity_R
0.82
gMVP
0.94

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.

Other links and lift over

dbSNP: rs750068778; hg19: chr11-102661243; API