17-68250200-C-T

Variant names:

• chr17-68250200-C-T
• rs532820909
• NM_016627.5:c.13C>T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001346481.1(AMZ2):​c.-100C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000285 in 1,612,340 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000030 (1 hom.)
• Consequence: AMZ2 NM_001346481.1 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.191

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.05985096).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AMZ2	NM_016627.5	c.13C>T	p.Arg5Trp	missense_variant	Exon 2 of 7	ENST00000359904.8	NP_057711.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AMZ2	ENST00000359904.8	c.13C>T	p.Arg5Trp	missense_variant	Exon 2 of 7	2	NM_016627.5	ENSP00000352976.3

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152096 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000560 AC: 14 AN: 250142 Hom.: 0 AF XY: 0.0000813 AC XY: 11 AN XY: 135308

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: 0.000427

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000882

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000301 AC: 44 AN: 1460126 Hom.: 1 Cov.: 29 AF XY: 0.0000399 AC XY: 29 AN XY: 726302

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000225

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000360

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000900

Gnomad4 OTH exome AF: 0.0000332

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152214 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74430

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000626 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.0000824 AC: 10

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 22, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.13C>T (p.R5W) alteration is located in exon 2 (coding exon 1) of the AMZ2 gene. This alteration results from a C to T substitution at nucleotide position 13, causing the arginine (R) at amino acid position 5 to be replaced by a tryptophan (W). 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	0.089
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	19
DANN	Benign	0.55
DEOGEN2	Benign	0.090	T;T;T;T;T;.;T;T;T;T;T;.
Eigen	Benign	-0.43
Eigen_PC	Benign	-0.63
FATHMM_MKL	Benign	0.081	N
LIST_S2	Benign	0.77	.;T;T;.;.;T;T;T;T;.;.;T
M_CAP	Benign	0.0097	T
MetaRNN	Benign	0.060	T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.4	M;.;M;M;M;M;.;.;.;M;M;.
PrimateAI	Benign	0.25	T
PROVEAN	Uncertain	-3.7	D;.;.;.;D;D;.;.;.;.;.;.
REVEL	Benign	0.037
Sift	Uncertain	0.0010	D;.;.;.;D;D;.;.;.;.;.;.
Sift4G	Uncertain	0.0040	D;D;D;D;D;D;D;D;D;D;D;D
Polyphen		0.99	D;.;D;D;D;.;.;.;.;D;D;.
Vest4		0.38
MutPred		0.36		Loss of MoRF binding (P = 0.0189);Loss of MoRF binding (P = 0.0189);Loss of MoRF binding (P = 0.0189);Loss of MoRF binding (P = 0.0189);Loss of MoRF binding (P = 0.0189);Loss of MoRF binding (P = 0.0189);Loss of MoRF binding (P = 0.0189);Loss of MoRF binding (P = 0.0189);Loss of MoRF binding (P = 0.0189);Loss of MoRF binding (P = 0.0189);Loss of MoRF binding (P = 0.0189);Loss of MoRF binding (P = 0.0189);
MVP		0.44
MPC		0.33
ClinPred		0.37	T
GERP RS		1.6
Varity_R		0.13
gMVP		0.33

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs532820909; hg19: chr17-66246341; COSMIC: COSV63083369; COSMIC: COSV63083369;