Variant 3-28324092-G-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.1129C>T(p.Pro377Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,458,902 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

AZI2
NM_022461.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.820

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:

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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=0.056280673).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AZI2	NM_022461.5 linkuse as main transcript	c.1129C>T	p.Pro377Ser	missense_variant	8/8	ENST00000479665.6	NP_071906.1	Q9H6S1-1
CMC1	NM_182523.2 linkuse as main transcript	c.*4463G>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.1129C>T	p.Pro377Ser	missense_variant	8/8	2	NM_022461.5	ENSP00000419371.1	Q9H6S1-1
CMC1	ENST00000466830.6 linkuse as main transcript	c.*4463G>A		3_prime_UTR_variant	4/4	1	NM_182523.2	ENSP00000418348.1	Q7Z7K0
AZI2	ENST00000295748.7 linkuse as main transcript	n.1388C>T		non_coding_transcript_exon_variant	9/9	1
AZI2	ENST00000429369.5 linkuse as main transcript	c.157+2740C>T		intron_variant		3		ENSP00000403133.1	H7C1Z1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1458902

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

725742

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:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.01e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

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

Sep 24, 2024

The c.1129C>T (p.P377S) alteration is located in exon 8 (coding exon 7) of the AZI2 gene. This alteration results from a C to T substitution at nucleotide position 1129, causing the proline (P) at amino acid position 377 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

0.075

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Benign

-0.43

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Benign

0.028

Eigen

Benign

-0.22

Eigen_PC

Benign

-0.095

FATHMM_MKL

Benign

0.54

LIST_S2

Benign

0.69

M_CAP

Benign

0.0031

MetaRNN

Benign

0.056

MetaSVM

Benign

-0.89

MutationAssessor

Uncertain

2.1

PrimateAI

Benign

0.29

PROVEAN

Benign

0.060

REVEL

Benign

0.13

Sift

Benign

0.14

Sift4G

Benign

1.0

Polyphen

0.0010

Vest4

0.063

MutPred

0.16

Loss of catalytic residue at P376 (P = 0.0165);

MVP

0.42

MPC

0.18

ClinPred

0.090

GERP RS

3.2

Varity_R

0.021

gMVP

0.33

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over