17-68250225-C-T

Variant names:

• chr17-68250225-C-T
• rs781919236
• NM_016627.5:c.38C>T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_016627.5(AMZ2):​c.38C>T​(p.Thr13Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000248 in 1,614,048 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict 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: 0.0000014 (0 hom.)
• Consequence: AMZ2 NM_016627.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.244

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.10334793).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AMZ2	NM_016627.5	c.38C>T	p.Thr13Ile	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.38C>T	p.Thr13Ile	missense_variant	Exon 2 of 7	2	NM_016627.5	ENSP00000352976.3

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152198 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00000796 AC: 2 AN: 251400 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135882

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.0000289

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461850 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 727224

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152198 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74356

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.0000282 Hom.: 0

Bravo AF: 0.0000264

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

Mar 15, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.38C>T (p.T13I) 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 38, causing the threonine (T) at amino acid position 13 to be replaced by an isoleucine (I). 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	0.14
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	20
DANN	Benign	0.72
DEOGEN2	Benign	0.059	T;T;T;T;T;.;T;T;T;T;T;.
Eigen	Benign	-0.36
Eigen_PC	Benign	-0.39
FATHMM_MKL	Benign	0.21	N
LIST_S2	Benign	0.42	.;T;T;.;.;T;T;T;T;.;.;T
M_CAP	Benign	0.0070	T
MetaRNN	Benign	0.10	T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.5	M;.;M;M;M;M;.;.;.;M;M;.
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-1.8	N;.;.;.;N;N;.;.;.;.;.;.
REVEL	Benign	0.080
Sift	Benign	0.071	T;.;.;.;T;T;.;.;.;.;.;.
Sift4G	Benign	0.27	T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.67	P;.;P;P;P;.;.;.;.;P;P;.
Vest4		0.12
MutPred		0.26		Loss of disorder (P = 0.0587);Loss of disorder (P = 0.0587);Loss of disorder (P = 0.0587);Loss of disorder (P = 0.0587);Loss of disorder (P = 0.0587);Loss of disorder (P = 0.0587);Loss of disorder (P = 0.0587);Loss of disorder (P = 0.0587);Loss of disorder (P = 0.0587);Loss of disorder (P = 0.0587);Loss of disorder (P = 0.0587);Loss of disorder (P = 0.0587);
MVP		0.28
MPC		0.11
ClinPred		0.11	T
GERP RS		3.7
Varity_R		0.062
gMVP		0.35

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs781919236; hg19: chr17-66246366;