Variant 3-28324128-T-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_022461.5(AZI2):c.1093A>T(p.Thr365Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000534 in 1,610,502 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000060 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000053 ( 1 hom. )

Consequence

AZI2
NM_022461.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.332

Variant links:

Genes affected

AZI2 (HGNC:24002): (5-azacytidine induced 2) AZI2, or NAP1, contributes to the activation of NFKB (see MIM 164011)-dependent gene expression by activating IKK-related kinases, such as NAK (TBK1; MIM 604834) (Fujita et al., 2003 [PubMed 14560022]).[supplied by OMIM, Mar 2008]

AZI2 links:

CMC1 (HGNC:28783): (C-X9-C motif containing 1) Predicted to enable metal ion binding activity. Located in mitochondrion. [provided by Alliance of Genome Resources, Apr 2022]

CMC1 links:

AZI2 (HGNC:):

AZI2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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=0.014858007).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AZI2	NM_022461.5 linkuse as main transcript	c.1093A>T	p.Thr365Ser	missense_variant	8/8	ENST00000479665.6	NP_071906.1	Q9H6S1-1
CMC1	NM_182523.2 linkuse as main transcript	c.*4499T>A		3_prime_UTR_variant	4/4	ENST00000466830.6	NP_872329.1	Q7Z7K0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
AZI2	ENST00000479665.6 linkuse as main transcript	c.1093A>T	p.Thr365Ser	missense_variant	8/8	2	NM_022461.5	ENSP00000419371.1	Q9H6S1-1
CMC1	ENST00000466830.6 linkuse as main transcript	c.*4499T>A		3_prime_UTR_variant	4/4	1	NM_182523.2	ENSP00000418348.1	Q7Z7K0
AZI2	ENST00000295748.7 linkuse as main transcript	n.1352A>T		non_coding_transcript_exon_variant	9/9	1
AZI2	ENST00000429369.5 linkuse as main transcript	c.157+2704A>T		intron_variant		3		ENSP00000403133.1	H7C1Z1

Frequencies

GnomAD3 genomes

AF:

0.0000596

AC:

AN:

151044

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000663

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000188

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000742

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000440

AC:

AN:

250140

Hom.:

AF XY:

0.0000666

AC XY:

AN XY:

135194

show subpopulations

Gnomad AFR exome

AF:

0.0000619

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000980

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000621

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000528

AC:

AN:

1459340

Hom.:

Cov.:

AF XY:

0.0000579

AC XY:

AN XY:

725954

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:

0.000221

Gnomad4 FIN exome

AF:

0.0000936

Gnomad4 NFE exome

AF:

0.0000450

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000595

AC:

AN:

151162

Hom.:

Cov.:

AF XY:

0.0000677

AC XY:

AN XY:

73876

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.0000662

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000188

Gnomad4 NFE

AF:

0.0000743

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000959

Hom.:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000659

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 20, 2024

The c.1093A>T (p.T365S) alteration is located in exon 8 (coding exon 7) of the AZI2 gene. This alteration results from a A to T substitution at nucleotide position 1093, causing the threonine (T) at amino acid position 365 to be replaced by a serine (S). 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

0.083

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.64

CADD

Benign

DANN

Benign

0.85

DEOGEN2

Benign

0.030

Eigen

Benign

-0.85

Eigen_PC

Benign

-0.73

FATHMM_MKL

Benign

0.23

LIST_S2

Benign

0.41

M_CAP

Benign

0.0021

MetaRNN

Benign

0.015

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.41

PrimateAI

Benign

0.32

PROVEAN

Benign

0.38

REVEL

Benign

0.021

Sift

Benign

0.55

Sift4G

Benign

0.98

Polyphen

0.0010

Vest4

0.049

MutPred

0.15

Gain of glycosylation at T365 (P = 0.0052);

MVP

0.19

MPC

0.15

ClinPred

0.010

GERP RS

0.94

Varity_R

0.049

gMVP

0.078

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