rs1433832678

Variant names:

• chr12-131840812-A-C
• rs1433832678
• NM_016155.7:c.662A>C

Your query was ambiguous. Multiple possible variants found:

• chr12-131840812-A-C
• chr12-131840812-A-T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_016155.7(MMP17):​c.662A>C​(p.Asp221Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 34)
• Consequence: MMP17 NM_016155.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.31
• Publications: 0 publications found

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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.929

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MMP17	NM_016155.7	c.662A>C	p.Asp221Ala	missense_variant	Exon 4 of 10	ENST00000360564.5	NP_057239.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MMP17	ENST00000360564.5	c.662A>C	p.Asp221Ala	missense_variant	Exon 4 of 10	1	NM_016155.7	ENSP00000353767.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 34

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 06, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.662A>C (p.D221A) alteration is located in exon 4 (coding exon 4) of the MMP17 gene. This alteration results from a A to C substitution at nucleotide position 662, causing the aspartic acid (D) at amino acid position 221 to be replaced by an alanine (A). 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	Uncertain	0.42
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.040
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.30	T;.;.;T
Eigen	Pathogenic	0.72
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D;T;D;D
M_CAP	Benign	0.072	D
MetaRNN	Pathogenic	0.93	D;D;D;D
MetaSVM	Benign	-0.51	T
MutationAssessor	Pathogenic	3.0	M;.;.;.
PhyloP100		7.3
PrimateAI	Uncertain	0.56	T
PROVEAN	Pathogenic	-7.2	D;D;D;D
REVEL	Uncertain	0.54
Sift	Uncertain	0.0010	D;D;D;D
Sift4G	Uncertain	0.013	D;D;D;D
Polyphen		1.0	D;.;.;.
Vest4		0.89
MutPred		0.74		Gain of catalytic residue at H216 (P = 0);.;.;.;
MVP		0.76
MPC		0.59
ClinPred		0.99	D
GERP RS		4.5
Varity_R		0.72
gMVP		0.89
Mutation Taster		=46/54	disease causing

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: rs1433832678; hg19: chr12-132325357;