Genetic Variant AMZ2:p.Val171Met (chr17-68251103-G-A) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

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 (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.000021 ( 0 hom. )

Consequence

AMZ2
NM_016627.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.38

Variant links:

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]

AMZ2 links:

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ACMG classification

Classification made for transcript

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=0.3759464).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AMZ2	NM_016627.5 link	c.511G>A	p.Val171Met	missense_variant	Exon 4 of 7	ENST00000359904.8	NP_057711.3	Q86W34-4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AMZ2	ENST00000359904.8 link	c.511G>A	p.Val171Met	missense_variant	Exon 4 of 7	2	NM_016627.5	ENSP00000352976.3		Q86W34-4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000797

AC:

AN:

250900

Hom.:

AF XY:

0.0000148

AC XY:

AN XY:

135580

show subpopulations

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 SAS 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:

AN:

1461476

Hom.:

Cov.:

AF XY:

0.0000179

AC XY:

AN XY:

727006

show subpopulations

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:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000216

Gnomad4 OTH exome

AF:

0.000116

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

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

BayesDel_noAF

Benign

-0.20

CADD

Uncertain

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

LIST_S2

Uncertain

0.92

.;D;D;.;.;D;D;D;D;D;.;.;D

M_CAP

Benign

0.034

MetaRNN

Benign

0.38

T;T;T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.69

MutationAssessor

Uncertain

2.7

M;.;M;M;M;.;.;.;.;.;M;M;.

PrimateAI

Uncertain

0.61

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

GERP RS

2.5

Varity_R

0.060

gMVP

0.61

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over