8-88056213-G-A

Position:

• chr8-88056213-G-A

Variant summary

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

The NM_005941.5(MMP16):​c.1288C>T​(p.Leu430Phe) variant causes a missense change. The variant allele was found at a frequency of 0.00000207 in 1,448,788 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: MMP16 NM_005941.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.66

Genes affected

MMP16 (HGNC:7162): (matrix metallopeptidase 16) Proteins of the matrix metalloproteinase (MMP) 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. Most MMP's are secreted as inactive proproteins which are activated when cleaved by extracellular proteinases. The encoded protein activates MMP2 by cleavage. This gene was once referred to as MT-MMP2, but was renamed as MT-MMP3 or MMP16. [provided by RefSeq, Oct 2010]

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=0.115516394).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MMP16	NM_005941.5	c.1288C>T	p.Leu430Phe	missense_variant	8/10	ENST00000286614.11	NP_005932.2
MMP16	XM_024447154.2	c.499C>T	p.Leu167Phe	missense_variant	5/7		XP_024302922.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MMP16	ENST00000286614.11	c.1288C>T	p.Leu430Phe	missense_variant	8/10	1	NM_005941.5	ENSP00000286614.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000207 AC: 3 AN: 1448788 Hom.: 0 Cov.: 29 AF XY: 0.00000416 AC XY: 3 AN XY: 720866

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000118

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000334

GnomAD4 genome Cov.: 32

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

Sep 11, 2024

The c.1288C>T (p.L430F) alteration is located in exon 8 (coding exon 8) of the MMP16 gene. This alteration results from a C to T substitution at nucleotide position 1288, causing the leucine (L) at amino acid position 430 to be replaced by a phenylalanine (F). 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	0.083
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.042	T
Eigen	Benign	-0.033
Eigen_PC	Benign	0.22
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.74	T
M_CAP	Benign	0.0072	T
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-0.66	T
MutationAssessor	Benign	1.3	L
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	0.93	N
REVEL	Benign	0.12
Sift	Benign	0.39	T
Sift4G	Benign	0.65	T
Polyphen		0.087	B
Vest4		0.15
MutPred		0.66		Loss of stability (P = 0.0805);
MVP		0.25
MPC		0.98
ClinPred		0.63	D
GERP RS		5.9
Varity_R		0.065
gMVP		0.50

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: rs1186747588; hg19: chr8-89068441;