16-58026375-G-T

Variant names:

• chr16-58026375-G-T
• rs540813875
• NM_002428.4:c.25G>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_002428.4(MMP15):​c.25G>T​(p.Gly9*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000818 in 1,222,010 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 8.2e-7 (0 hom.)
• Consequence: MMP15 NM_002428.4 stop_gained
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.06
• Publications: 0 publications found

Genes affected

MMP15 (HGNC:7161): (matrix metallopeptidase 15) This gene encodes a member of the peptidase M10 family and membrane-type subfamily 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. Members of this subfamily contain a transmembrane domain suggesting that these proteins are expressed at the cell surface rather than secreted. The encoded preproprotein is proteolytically processed to generate the mature protease. This protein may play a role in cancer progression. [provided by RefSeq, Jan 2016]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MMP15	NM_002428.4	c.25G>T	p.Gly9*	stop_gained	Exon 1 of 10	ENST00000219271.4	NP_002419.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MMP15	ENST00000219271.4	c.25G>T	p.Gly9*	stop_gained	Exon 1 of 10	1	NM_002428.4	ENSP00000219271.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 8.18e-7 AC: 1 AN: 1222010 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 595960

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 23940

American (AMR) AF: 0.00 AC: 0 AN: 10628

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16902

East Asian (EAS) AF: 0.00 AC: 0 AN: 27568

South Asian (SAS) AF: 0.0000184 AC: 1 AN: 54246

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 30678

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3408

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1004546

Other (OTH) AF: 0.00 AC: 0 AN: 50094

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.29
CADD	Pathogenic	37
DANN	Uncertain	0.99
Eigen	Uncertain	0.68
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Benign	0.42	N
PhyloP100		1.1
Vest4		0.48
GERP RS		1.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

Other links and lift over

dbSNP: rs540813875; hg19: chr16-58060279;