11-102791492-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_002421.4(MMP1):c.1037A>C(p.Asn346Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000114 in 1,612,040 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000085 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00012 (0 hom.)
• Consequence: MMP1 NM_002421.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.598

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1046153).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MMP1	NM_002421.4	c.1037A>C	p.Asn346Thr	missense_variant	8/10	ENST00000315274.7
WTAPP1	NR_038390.1	n.390-1653T>G		intron_variant, non_coding_transcript_variant
MMP1	NM_001145938.2	c.839A>C	p.Asn280Thr	missense_variant	8/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MMP1	ENST00000315274.7	c.1037A>C	p.Asn346Thr	missense_variant	8/10	1	NM_002421.4	P1
WTAPP1	ENST00000371455.7	n.325-6532T>G		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes AF: 0.0000854 AC: 13 AN: 152202 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

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: 0.00316

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000844 AC: 21 AN: 248854 Hom.: 0 AF XY: 0.0000893 AC XY: 12 AN XY: 134404

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000118

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000232

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000798

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.000116 AC: 170 AN: 1459838 Hom.: 0 Cov.: 31 AF XY: 0.000125 AC XY: 91 AN XY: 726094

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000904

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000117

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000129

Gnomad4 OTH exome AF: 0.000133

GnomAD4 genome AF: 0.0000854 AC: 13 AN: 152202 Hom.: 0 Cov.: 33 AF XY: 0.0000538 AC XY: 4 AN XY: 74356

Gnomad4 AFR AF: 0.0000241

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: 0.000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000991 Hom.: 0

Bravo AF: 0.0000756

ExAC AF: 0.0000824 AC: 10

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000273

EpiControl AF: 0.000178

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

Feb 22, 2023

The c.1037A>C (p.N346T) alteration is located in exon 8 (coding exon 8) of the MMP1 gene. This alteration results from a A to C substitution at nucleotide position 1037, causing the asparagine (N) at amino acid position 346 to be replaced by a threonine (T). 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	0.11
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.66
Cadd	Benign	10
Dann	Benign	0.92
DEOGEN2	Benign	0.15	T
Eigen	Benign	-0.95
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.33	T
M_CAP	Benign	0.0049	T
MetaRNN	Benign	0.10	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.4	L
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.24	T
PROVEAN	Uncertain	-3.0	D
REVEL	Benign	0.018
Sift	Benign	0.11	T
Sift4G	Benign	0.33	T
Polyphen		0.050	B
Vest4		0.25
MutPred		0.49		Loss of catalytic residue at N346 (P = 0.0762);
MVP		0.23
MPC		0.0075
ClinPred		0.016	T
GERP RS		-1.3
Varity_R		0.16
gMVP		0.55

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: rs201210902; hg19: chr11-102662223;