chr1-159016640-G-A

Position:

• chr1-159016640-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001376587.1(IFI16):​c.489G>A​(p.Met163Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,866 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: IFI16 NM_001376587.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.23

Genes affected

IFI16 (HGNC:5395): (interferon gamma inducible protein 16) This gene encodes a member of the HIN-200 (hematopoietic interferon-inducible nuclear antigens with 200 amino acid repeats) family of cytokines. The encoded protein contains domains involved in DNA binding, transcriptional regulation, and protein-protein interactions. The protein localizes to the nucleoplasm and nucleoli, and interacts with p53 and retinoblastoma-1. It modulates p53 function, and inhibits cell growth in the Ras/Raf signaling pathway. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Apr 2011]

ACMG classification

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=0.062554896).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IFI16	NM_001376587.1	c.489G>A	p.Met163Ile	missense_variant	4/12	ENST00000295809.12	NP_001363516.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IFI16	ENST00000295809.12	c.489G>A	p.Met163Ile	missense_variant	4/12	5	NM_001376587.1	ENSP00000295809	A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461866 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727228

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000312 Hom.: 0

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

Jun 21, 2023

The c.489G>A (p.M163I) alteration is located in exon 4 (coding exon 3) of the IFI16 gene. This alteration results from a G to A substitution at nucleotide position 489, causing the methionine (M) at amino acid position 163 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	0.21
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	0.21
DANN	Benign	0.67
DEOGEN2	Benign	0.023	T;T;.;.;T;.;.;T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.019	N
LIST_S2	Benign	0.78	T;T;.;T;T;T;T;T
M_CAP	Benign	0.0030	T
MetaRNN	Benign	0.063	T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	1.8	.;.;L;L;L;L;.;.
MutationTaster	Benign	1.0	N;N;N;N;N;N;N
PROVEAN	Benign	-1.5	N;N;N;N;N;N;N;N
REVEL	Benign	0.037
Sift	Benign	0.12	T;T;T;T;T;T;T;T
Sift4G	Benign	0.48	T;T;T;T;T;T;T;T
Polyphen		0.0	.;.;B;B;B;.;.;.
Vest4		0.12, 0.073, 0.066
MutPred		0.25		Gain of glycosylation at S160 (P = 0.0831);Gain of glycosylation at S160 (P = 0.0831);Gain of glycosylation at S160 (P = 0.0831);Gain of glycosylation at S160 (P = 0.0831);Gain of glycosylation at S160 (P = 0.0831);Gain of glycosylation at S160 (P = 0.0831);.;.;
MVP		0.17
MPC		0.19
ClinPred		0.023	T
GERP RS		-2.8
Varity_R		0.15
gMVP		0.057

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

Other links and lift over

dbSNP: rs1652947593; hg19: chr1-158986430;