rs3213690

chr17-68250275-A-Gchr17-68250275-A-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_016627.5(AMZ2):c.88A>G(p.Asn30Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.69 in 1,614,014 control chromosomes in the GnomAD database, including 388,871 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.75 (44212 hom., cov: 32)
  • Exomes 𝑓: 0.68 (344659 hom.)
• Consequence: AMZ2 NM_016627.5 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.851

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

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=9.033858E-7).
• BP6: Variant 17-68250275-A-G is Benign according to our data. Variant chr17-68250275-A-G is described in ClinVar as [Benign]. Clinvar id is 3059188.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.92 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AMZ2	NM_016627.5	c.88A>G	p.Asn30Asp	missense_variant	2/7	ENST00000359904.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AMZ2	ENST00000359904.8	c.88A>G	p.Asn30Asp	missense_variant	2/7	2	NM_016627.5	P1

Frequencies

GnomAD3 genomes AF: 0.752 AC: 114351 AN: 152012 Hom.: 44140 Cov.: 32

Gnomad AFR AF: 0.928

Gnomad AMI AF: 0.676

Gnomad AMR AF: 0.792

Gnomad ASJ AF: 0.694

Gnomad EAS AF: 0.761

Gnomad SAS AF: 0.749

Gnomad FIN AF: 0.577

Gnomad MID AF: 0.684

Gnomad NFE AF: 0.668

Gnomad OTH AF: 0.741

GnomAD3 exomes AF: 0.718 AC: 180471 AN: 251468 Hom.: 66043 AF XY: 0.709 AC XY: 96358 AN XY: 135908

Gnomad AFR exome AF: 0.935

Gnomad AMR exome AF: 0.841

Gnomad ASJ exome AF: 0.677

Gnomad EAS exome AF: 0.780

Gnomad SAS exome AF: 0.740

Gnomad FIN exome AF: 0.576

Gnomad NFE exome AF: 0.664

Gnomad OTH exome AF: 0.703

GnomAD4 exome AF: 0.684 AC: 999672 AN: 1461880 Hom.: 344659 Cov.: 73 AF XY: 0.684 AC XY: 497400 AN XY: 727242

Gnomad4 AFR exome AF: 0.939

Gnomad4 AMR exome AF: 0.834

Gnomad4 ASJ exome AF: 0.684

Gnomad4 EAS exome AF: 0.742

Gnomad4 SAS exome AF: 0.738

Gnomad4 FIN exome AF: 0.579

Gnomad4 NFE exome AF: 0.668

Gnomad4 OTH exome AF: 0.700

GnomAD4 genome AF: 0.753 AC: 114484 AN: 152134 Hom.: 44212 Cov.: 32 AF XY: 0.751 AC XY: 55833 AN XY: 74356

Gnomad4 AFR AF: 0.928

Gnomad4 AMR AF: 0.793

Gnomad4 ASJ AF: 0.694

Gnomad4 EAS AF: 0.761

Gnomad4 SAS AF: 0.749

Gnomad4 FIN AF: 0.577

Gnomad4 NFE AF: 0.668

Gnomad4 OTH AF: 0.742

Alfa AF: 0.689 Hom.: 79689

Bravo AF: 0.777

TwinsUK AF: 0.661 AC: 2452

ALSPAC AF: 0.677 AC: 2608

ESP6500AA AF: 0.925 AC: 4075

ESP6500EA AF: 0.674 AC: 5793

ExAC AF: 0.718 AC: 87162

Asia WGS AF: 0.785 AC: 2729 AN: 3478

EpiCase AF: 0.673

EpiControl AF: 0.674

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

AMZ2-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 17, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.047
BayesDel_addAF	Benign	-0.77	T
BayesDel_noAF	Benign	-0.74
Cadd	Benign	11
Dann	Benign	0.94
DEOGEN2	Benign	0.0019	T;T;T;T;T;.;T;T;T;T;T;.
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.0057	N
MetaRNN	Benign	9.0e-7	T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-2.5	N;.;N;N;N;N;.;.;.;N;N;.
MutationTaster	Benign	1.0	P;P;P;P;P;P;P
PrimateAI	Benign	0.35	T
PROVEAN	Benign	1.3	N;.;.;.;N;N;.;.;.;.;.;.
REVEL	Benign	0.027
Sift	Benign	1.0	T;.;.;.;T;T;.;.;.;.;.;.
Sift4G	Benign	1.0	T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.0	B;.;B;B;B;.;.;.;.;B;B;.
Vest4		0.011
MPC		0.10
ClinPred		0.0031	T
GERP RS		1.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.11
gMVP		0.13

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

Other links and lift over

dbSNP: rs3213690; hg19: chr17-66246416; COSMIC: COSV63082480; COSMIC: COSV63082480;