12-131828606-G-C

Position:

• chr12-131828606-G-C

Variant summary

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

The NM_016155.7(MMP17):​c.112G>C​(p.Ala38Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000027 in 740,574 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: MMP17 NM_016155.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.834

Genes affected

MMP17 (HGNC:7163): (matrix metallopeptidase 17) 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 is unique among the membrane-type matrix metalloproteinases in that it is anchored to the cell membrane via a glycosylphosphatidylinositol (GPI) anchor. Elevated expression of the encoded protein has been observed in osteoarthritis and multiple human cancers. [provided by RefSeq, Jan 2016]

MMP17 (HGNC:):

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=0.122801304).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MMP17	NM_016155.7	c.112G>C	p.Ala38Pro	missense_variant	1/10	ENST00000360564.5	NP_057239.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MMP17	ENST00000360564.5	c.112G>C	p.Ala38Pro	missense_variant	1/10	1	NM_016155.7	ENSP00000353767.1
MMP17	ENST00000535004.2	n.112G>C		non_coding_transcript_exon_variant	1/10	3		ENSP00000445620.2
MMP17	ENST00000545671.6	n.112G>C		non_coding_transcript_exon_variant	1/4	3		ENSP00000444603.2
MMP17	ENST00000545790.6	n.112G>C		non_coding_transcript_exon_variant	1/11	2		ENSP00000441710.2

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.00000270 AC: 2 AN: 740574 Hom.: 0 Cov.: 10 AF XY: 0.00 AC XY: 0 AN XY: 349762

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000225

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

Bravo AF: 0.0000151

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 15, 2023

The c.112G>C (p.A38P) alteration is located in exon 1 (coding exon 1) of the MMP17 gene. This alteration results from a G to C substitution at nucleotide position 112, causing the alanine (A) at amino acid position 38 to be replaced by a proline (P). 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	0.097
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.036	T
Eigen	Benign	-0.58
Eigen_PC	Benign	-0.66
FATHMM_MKL	Benign	0.20	N
LIST_S2	Benign	0.43	T
M_CAP	Benign	0.042	D
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.90	L
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	0.87	N
REVEL	Benign	0.082
Sift	Uncertain	0.017	D
Sift4G	Benign	0.34	T
Polyphen		0.96	D
Vest4		0.16
MutPred		0.33		Gain of catalytic residue at G36 (P = 0);
MVP		0.33
MPC		0.26
ClinPred		0.56	D
GERP RS		0.39
Varity_R		0.082
gMVP		0.42

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1475082936; hg19: chr12-132313151;