11-102791397-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_002421.4(MMP1):c.1132G>A(p.Asp378Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000136 in 1,613,910 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000096 (0 hom.)
• Consequence: MMP1 NM_002421.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.261

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)

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM1: In a binding_site (size 0) in uniprot entity MMP1_HUMAN
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MMP1	NM_002421.4	c.1132G>A	p.Asp378Asn	missense_variant	8/10	ENST00000315274.7
WTAPP1	NR_038390.1	n.390-1748C>T		intron_variant, non_coding_transcript_variant
MMP1	NM_001145938.2	c.934G>A	p.Asp312Asn	missense_variant	8/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MMP1	ENST00000315274.7	c.1132G>A	p.Asp378Asn	missense_variant	8/10	1	NM_002421.4	P1
WTAPP1	ENST00000371455.7	n.325-6627C>T		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 152188 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000796 AC: 2 AN: 251404 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135882

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000958 AC: 14 AN: 1461722 Hom.: 0 Cov.: 31 AF XY: 0.00000963 AC XY: 7 AN XY: 727160

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000894

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000374

Gnomad4 NFE exome AF: 0.00000540

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome AF: 0.0000526 AC: 8 AN: 152188 Hom.: 0 Cov.: 33 AF XY: 0.0000404 AC XY: 3 AN XY: 74342

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000393

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.000113

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 09, 2023

The c.1132G>A (p.D378N) alteration is located in exon 8 (coding exon 8) of the MMP1 gene. This alteration results from a G to A substitution at nucleotide position 1132, causing the aspartic acid (D) at amino acid position 378 to be replaced by an asparagine (N). 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	0.21
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.51
Cadd	Benign	19
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.18	T
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.77	T
M_CAP	Benign	0.040	D
MetaRNN	Uncertain	0.66	D
MetaSVM	Benign	-1.1	T
MutationAssessor	Pathogenic	3.3	M
MutationTaster	Benign	1.0	D
PrimateAI	Benign	0.47	T
PROVEAN	Uncertain	-4.2	D
REVEL	Benign	0.23
Sift	Benign	0.057	T
Sift4G	Uncertain	0.034	D
Polyphen		1.0	D
Vest4		0.39
MutPred		0.84		Loss of sheet (P = 0.0817);
MVP		0.62
MPC		0.017
ClinPred		0.97	D
GERP RS		4.9
Varity_R		0.52
gMVP		0.88

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

Other links and lift over

dbSNP: rs745361439; hg19: chr11-102662128; COSMIC: COSV105875899;