8-88116521-T-A

Position:

• chr8-88116521-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_005941.5(MMP16):​c.1069A>T​(p.Met357Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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: not found (cov: 32)
• Consequence: MMP16 NM_005941.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.80

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2769463).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MMP16	NM_005941.5	c.1069A>T	p.Met357Leu	missense_variant	6/10	ENST00000286614.11	NP_005932.2
MMP16	XM_024447154.2	c.280A>T	p.Met94Leu	missense_variant	3/7		XP_024302922.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MMP16	ENST00000286614.11	c.1069A>T	p.Met357Leu	missense_variant	6/10	1	NM_005941.5	ENSP00000286614	P1
MMP16	ENST00000544227.5	n.1069A>T		non_coding_transcript_exon_variant	6/8	1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

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

May 30, 2024

The c.1069A>T (p.M357L) alteration is located in exon 6 (coding exon 6) of the MMP16 gene. This alteration results from a A to T substitution at nucleotide position 1069, causing the methionine (M) at amino acid position 357 to be replaced by a leucine (L). 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	-0.23	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	21
DANN	Benign	0.97
DEOGEN2	Benign	0.13	T
Eigen	Benign	-0.048
Eigen_PC	Benign	0.17
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.0087	T
MetaRNN	Benign	0.28	T
MetaSVM	Benign	-0.70	T
MutationAssessor	Benign	0.53	N
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-2.2	N
REVEL	Benign	0.12
Sift	Benign	0.18	T
Sift4G	Benign	0.27	T
Polyphen		0.050	B
Vest4		0.40
MutPred		0.60		Gain of catalytic residue at M357 (P = 0.0117);
MVP		0.19
MPC		0.81
ClinPred		0.62	D
GERP RS		5.9
Varity_R		0.35
gMVP		0.54

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs1379083642; hg19: chr8-89128750;