chr3-28338017-G-A

Position:

• chr3-28338017-G-A

Variant summary

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

The NM_022461.5(AZI2):​c.359C>T​(p.Ser120Phe) variant causes a missense change. The variant allele was found at a frequency of 0.00000209 in 1,433,796 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: AZI2 NM_022461.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.86

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AZI2	NM_022461.5	c.359C>T	p.Ser120Phe	missense_variant	4/8	ENST00000479665.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AZI2	ENST00000479665.6	c.359C>T	p.Ser120Phe	missense_variant	4/8	2	NM_022461.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000209 AC: 3 AN: 1433796 Hom.: 0 Cov.: 28 AF XY: 0.00000140 AC XY: 1 AN XY: 712964

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000513

Gnomad4 SAS exome AF: 0.0000123

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 27, 2021

The c.359C>T (p.S120F) alteration is located in exon 4 (coding exon 3) of the AZI2 gene. This alteration results from a C to T substitution at nucleotide position 359, causing the serine (S) at amino acid position 120 to be replaced by a phenylalanine (F). 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	0.28
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.33
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.34	T;.;.;.;T
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.91	D;D;.;D;D
M_CAP	Benign	0.0047	T
MetaRNN	Uncertain	0.52	D;D;D;D;D
MetaSVM	Benign	-0.49	T
MutationAssessor	Uncertain	2.5	M;M;M;M;.
MutationTaster	Benign	0.97	D;D;D;D
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-2.0	N;N;N;N;N
REVEL	Uncertain	0.62
Sift	Benign	0.090	T;D;D;D;D
Sift4G	Uncertain	0.014	D;D;D;D;.
Polyphen		0.89	P;.;.;.;D
Vest4		0.50
MutPred		0.40		Gain of glycosylation at S118 (P = 0.01);Gain of glycosylation at S118 (P = 0.01);Gain of glycosylation at S118 (P = 0.01);Gain of glycosylation at S118 (P = 0.01);Gain of glycosylation at S118 (P = 0.01);
MVP		0.63
MPC		0.49
ClinPred		0.92	D
GERP RS		5.7
Varity_R		0.16
gMVP		0.39

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: rs1427262733; hg19: chr3-28379508;