1-159018529-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001376587.1(IFI16):c.850C>A(p.Pro284Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P284S) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: IFI16 NM_001376587.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.79

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.12735614).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IFI16	NM_001376587.1	c.850C>A	p.Pro284Thr	missense_variant	5/12	ENST00000295809.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IFI16	ENST00000295809.12	c.850C>A	p.Pro284Thr	missense_variant	5/12	5	NM_001376587.1	A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

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

Jan 17, 2024

The c.850C>A (p.P284T) alteration is located in exon 5 (coding exon 4) of the IFI16 gene. This alteration results from a C to A substitution at nucleotide position 850, causing the proline (P) at amino acid position 284 to be replaced by a threonine (T). 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	0.11
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.59
Cadd	Benign	11
Dann	Benign	0.97
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.022	N
M_CAP	Benign	0.0027	T
MetaRNN	Benign	0.13	T;T;T;T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	1.7	L;L;L;.;L;.
MutationTaster	Benign	1.0	N;N;N;N;N;N;N
PrimateAI	Benign	0.28	T
PROVEAN	Pathogenic	-5.2	D;D;D;D;D;D
REVEL	Benign	0.031
Sift	Benign	0.15	T;T;T;T;T;T
Sift4G	Benign	0.084	T;T;T;D;D;T
Polyphen		0.043	B;B;B;.;.;.
Vest4		0.20
MutPred		0.56		Gain of catalytic residue at P284 (P = 0.0876);Gain of catalytic residue at P284 (P = 0.0876);Gain of catalytic residue at P284 (P = 0.0876);.;Gain of catalytic residue at P284 (P = 0.0876);.;
MVP		0.23
MPC		0.32
ClinPred		0.17	T
GERP RS		-2.6
Varity_R		0.19
gMVP		0.026

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.

Other links and lift over

hg19: chr1-158988319;