17-68250209-G-A

Variant names:

• chr17-68250209-G-A
• rs77434249
• NM_016627.5:c.22G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_016627.5(AMZ2):​c.22G>A​(p.Glu8Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000744 in 1,613,768 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: AMZ2 NM_016627.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.75
• Publications: 0 publications found

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.076845676).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016627.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AMZ2	NM_016627.5	MANE Select	c.22G>A	p.Glu8Lys	missense	Exon 2 of 7	NP_057711.3
	AMZ2	NM_001033569.2		c.22G>A	p.Glu8Lys	missense	Exon 3 of 8	NP_001028741.1	Q86W34-4
	AMZ2	NM_001033570.2		c.22G>A	p.Glu8Lys	missense	Exon 3 of 8	NP_001028742.1	Q86W34-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AMZ2	ENST00000359904.8	TSL:2 MANE Select	c.22G>A	p.Glu8Lys	missense	Exon 2 of 7	ENSP00000352976.3	Q86W34-4
	AMZ2	ENST00000392720.6	TSL:1	c.22G>A	p.Glu8Lys	missense	Exon 3 of 8	ENSP00000376481.2	Q86W34-4
	AMZ2	ENST00000577985.5	TSL:1	c.22G>A	p.Glu8Lys	missense	Exon 1 of 6	ENSP00000464635.1	Q86W34-4

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152074 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251268 AF XY: 0.00

Gnomad AFR exome AF: 0.0000616

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000616 AC: 9 AN: 1461694 Hom.: 0 Cov.: 29 AF XY: 0.00000275 AC XY: 2 AN XY: 727148

African (AFR) AF: 0.0000598 AC: 2 AN: 33466

American (AMR) AF: 0.0000447 AC: 2 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86240

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53342

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5756

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111962

Other (OTH) AF: 0.0000331 AC: 2 AN: 60390

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152074 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74278

African (AFR) AF: 0.0000483 AC: 2 AN: 41394

American (AMR) AF: 0.0000654 AC: 1 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10588

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68008

Other (OTH) AF: 0.00 AC: 0 AN: 2086

Alfa AF: 0.000162 Hom.: 0

Bravo AF: 0.0000793

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	11
DANN	Benign	0.59
DEOGEN2	Benign	0.019	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.22	N
LIST_S2	Benign	0.69	T
M_CAP	Benign	0.0035	T
MetaRNN	Benign	0.077	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		1.8
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.067
Sift	Benign	0.085	T
Sift4G	Benign	0.15	T
Polyphen		0.15	B
Vest4		0.37
MutPred		0.29		Gain of MoRF binding (P = 0.0031)
MVP		0.20
MPC		0.12
ClinPred		0.064	T
GERP RS		-1.0
PromoterAI		0.0078	Neutral
Varity_R		0.041
gMVP		0.36
Mutation Taster		=95/5	polymorphism

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

Other links and lift over

dbSNP: rs77434249; hg19: chr17-66246350; COSMIC: COSV63083548; COSMIC: COSV63083548;