17-68251103-G-A

Variant names:

• chr17-68251103-G-A
• rs782012937
• NM_016627.5:c.511G>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_016627.5(AMZ2):​c.511G>A​(p.Val171Met) variant causes a missense change. The variant allele was found at a frequency of 0.0000212 in 1,461,476 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V171L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000021 (0 hom.)
• Consequence: AMZ2 NM_016627.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.38

Genes affected

AMZ2 (HGNC:28041): (archaelysin family metallopeptidase 2) The protein encoded by this gene is a zinc metalloprotease that displays some activity against angiotensin-3. The encoded protein is inhibited by the aminopeptidase inhibitor amastatin, as well as by the general inhibitors o-phenanthroline and batimastat. Defects in this gene may be associated with lung tumorigenesis. [provided by RefSeq, Oct 2016]

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3759464).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AMZ2	NM_016627.5	c.511G>A	p.Val171Met	missense_variant	Exon 4 of 7	ENST00000359904.8	NP_057711.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AMZ2	ENST00000359904.8	c.511G>A	p.Val171Met	missense_variant	Exon 4 of 7	2	NM_016627.5	ENSP00000352976.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000797 AC: 2 AN: 250900 AF XY: 0.0000148

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000212 AC: 31 AN: 1461476 Hom.: 0 Cov.: 32 AF XY: 0.0000179 AC XY: 13 AN XY: 727006

African (AFR) AF: 0.00 AC: 0 AN: 33450

American (AMR) AF: 0.00 AC: 0 AN: 44676

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39672

South Asian (SAS) AF: 0.00 AC: 0 AN: 86096

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.0000216 AC: 24 AN: 1111900

Other (OTH) AF: 0.000116 AC: 7 AN: 60378

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 19, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.511G>A (p.V171M) alteration is located in exon 4 (coding exon 3) of the AMZ2 gene. This alteration results from a G to A substitution at nucleotide position 511, causing the valine (V) at amino acid position 171 to be replaced by a methionine (M). 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	0.49
BayesDel_addAF	Uncertain	0.017	T
BayesDel_noAF	Benign	-0.20
CADD	Uncertain	24
DANN	Benign	0.85
DEOGEN2	Benign	0.027	T;T;T;T;T;.;.;T;T;T;T;T;.
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Benign	0.71	D
LIST_S2	Uncertain	0.92	.;D;D;.;.;D;D;D;D;D;.;.;D
M_CAP	Benign	0.034	D
MetaRNN	Benign	0.38	T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.69	T
MutationAssessor	Uncertain	2.7	M;.;M;M;M;.;.;.;.;.;M;M;.
PhyloP100		4.4
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-1.2	N;.;.;.;N;N;.;.;.;.;.;.;.
REVEL	Benign	0.27
Sift	Uncertain	0.010	D;.;.;.;D;D;.;.;.;.;.;.;.
Sift4G	Uncertain	0.0060	D;D;D;D;D;D;D;D;D;D;D;D;D
Polyphen		1.0	D;.;D;D;D;.;.;.;.;.;D;D;.
Vest4		0.54
MutPred		0.48		Gain of catalytic residue at M175 (P = 0.0382);Gain of catalytic residue at M175 (P = 0.0382);Gain of catalytic residue at M175 (P = 0.0382);Gain of catalytic residue at M175 (P = 0.0382);Gain of catalytic residue at M175 (P = 0.0382);.;.;Gain of catalytic residue at M175 (P = 0.0382);Gain of catalytic residue at M175 (P = 0.0382);Gain of catalytic residue at M175 (P = 0.0382);Gain of catalytic residue at M175 (P = 0.0382);Gain of catalytic residue at M175 (P = 0.0382);Gain of catalytic residue at M175 (P = 0.0382);
MVP		0.57
MPC		0.48
ClinPred		0.58	D
GERP RS		2.5
Varity_R		0.060
gMVP		0.61
Mutation Taster		=83/17	polymorphism

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

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Other links and lift over

dbSNP: rs782012937; hg19: chr17-66247244;