1-159018233-C-T

Variant summary

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

The NM_001376587.1(IFI16):c.554C>T(p.Pro185Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000024 in 1,460,690 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 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: 0.000024 (0 hom.)
• Consequence: IFI16 NM_001376587.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.20

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=0.02868998).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IFI16	NM_001376587.1	c.554C>T	p.Pro185Leu	missense_variant	5/12	ENST00000295809.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IFI16	ENST00000295809.12	c.554C>T	p.Pro185Leu	missense_variant	5/12	5	NM_001376587.1	A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000479 AC: 12 AN: 250710 Hom.: 0 AF XY: 0.0000295 AC XY: 4 AN XY: 135614

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000291

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000490

Gnomad SAS exome AF: 0.0000655

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000240 AC: 35 AN: 1460690 Hom.: 0 Cov.: 32 AF XY: 0.0000234 AC XY: 17 AN XY: 726650

Gnomad4 AFR exome AF: 0.0000300

Gnomad4 AMR exome AF: 0.0000225

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000151

Gnomad4 SAS exome AF: 0.000139

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000450

Gnomad4 OTH exome AF: 0.000166

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000434 Hom.: 0

Bravo AF: 0.0000264

ExAC AF: 0.0000824 AC: 10

Asia WGS AF: 0.000866 AC: 3 AN: 3478

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

Mar 06, 2023

The c.554C>T (p.P185L) alteration is located in exon 5 (coding exon 4) of the IFI16 gene. This alteration results from a C to T substitution at nucleotide position 554, causing the proline (P) at amino acid position 185 to be replaced by a leucine (L). 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	0.093
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.69
Cadd	Benign	0.85
Dann	Benign	0.57
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.052	N
M_CAP	Benign	0.0035	T
MetaRNN	Benign	0.029	T;T;T;T;T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.11	N;N;N;.;N;.;.
MutationTaster	Benign	1.0	N;N;N;N;N;N;N
PrimateAI	Benign	0.21	T
PROVEAN	Benign	-1.9	N;N;N;N;N;N;D
REVEL	Benign	0.11
Sift	Benign	0.55	T;T;T;T;D;T;T
Sift4G	Benign	0.36	T;T;T;T;T;T;T
Polyphen		0.99	D;D;D;.;.;.;.
Vest4		0.17
MutPred		0.22		Loss of catalytic residue at P185 (P = 0.0172);Loss of catalytic residue at P185 (P = 0.0172);Loss of catalytic residue at P185 (P = 0.0172);.;Loss of catalytic residue at P185 (P = 0.0172);.;.;
MVP		0.32
MPC		0.32
ClinPred		0.12	T
GERP RS		-5.6
Varity_R		0.019
gMVP		0.036

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: rs751208160; hg19: chr1-158988023;