rs6940

Positions:

• chr1-159054878-A-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001376587.1(IFI16):​c.2335A>T​(p.Thr779Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.142 in 1,591,424 control chromosomes in the GnomAD database, including 18,168 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.17 (2454 hom., cov: 32)
  • Exomes 𝑓: 0.14 (15714 hom.)
• Consequence: IFI16 NM_001376587.1 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.07

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0050237477).
• BP6: Variant 1-159054878-A-T is Benign according to our data. Variant chr1-159054878-A-T is described in ClinVar as [Benign]. Clinvar id is 1230050.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.291 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IFI16	NM_001376587.1	c.2335A>T	p.Thr779Ser	missense_variant	12/12	ENST00000295809.12	NP_001363516.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IFI16	ENST00000295809.12	c.2335A>T	p.Thr779Ser	missense_variant	12/12	5	NM_001376587.1	ENSP00000295809	A2

Frequencies

GnomAD3 genomes AF: 0.167 AC: 25310 AN: 151990 Hom.: 2453 Cov.: 32

Gnomad AFR AF: 0.244

Gnomad AMI AF: 0.128

Gnomad AMR AF: 0.0879

Gnomad ASJ AF: 0.126

Gnomad EAS AF: 0.303

Gnomad SAS AF: 0.266

Gnomad FIN AF: 0.104

Gnomad MID AF: 0.105

Gnomad NFE AF: 0.133

Gnomad OTH AF: 0.150

GnomAD3 exomes AF: 0.153 AC: 37287 AN: 243370 Hom.: 3529 AF XY: 0.157 AC XY: 20699 AN XY: 131452

Gnomad AFR exome AF: 0.237

Gnomad AMR exome AF: 0.0681

Gnomad ASJ exome AF: 0.122

Gnomad EAS exome AF: 0.309

Gnomad SAS exome AF: 0.251

Gnomad FIN exome AF: 0.109

Gnomad NFE exome AF: 0.129

Gnomad OTH exome AF: 0.125

GnomAD4 exome AF: 0.139 AC: 200378 AN: 1439316 Hom.: 15714 Cov.: 26 AF XY: 0.142 AC XY: 101841 AN XY: 716578

Gnomad4 AFR exome AF: 0.247

Gnomad4 AMR exome AF: 0.0720

Gnomad4 ASJ exome AF: 0.121

Gnomad4 EAS exome AF: 0.244

Gnomad4 SAS exome AF: 0.246

Gnomad4 FIN exome AF: 0.112

Gnomad4 NFE exome AF: 0.128

Gnomad4 OTH exome AF: 0.152

GnomAD4 genome AF: 0.167 AC: 25327 AN: 152108 Hom.: 2454 Cov.: 32 AF XY: 0.164 AC XY: 12226 AN XY: 74374

Gnomad4 AFR AF: 0.244

Gnomad4 AMR AF: 0.0878

Gnomad4 ASJ AF: 0.126

Gnomad4 EAS AF: 0.303

Gnomad4 SAS AF: 0.265

Gnomad4 FIN AF: 0.104

Gnomad4 NFE AF: 0.133

Gnomad4 OTH AF: 0.147

Alfa AF: 0.140 Hom.: 1253

Bravo AF: 0.165

TwinsUK AF: 0.133 AC: 494

ALSPAC AF: 0.127 AC: 490

ESP6500AA AF: 0.231 AC: 1018

ESP6500EA AF: 0.132 AC: 1136

ExAC AF: 0.158 AC: 19172

Asia WGS AF: 0.282 AC: 978 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 29, 2020	This variant is associated with the following publications: (PMID: 25641891) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	12
DANN	Uncertain	0.98
DEOGEN2	Benign	0.020	T;.;.;T;.;.
Eigen	Benign	-0.33
Eigen_PC	Benign	-0.48
FATHMM_MKL	Benign	0.34	N
LIST_S2	Benign	0.57	T;.;T;T;T;T
MetaRNN	Benign	0.0050	T;T;T;T;T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	1.7	.;.;.;L;.;.
MutationTaster	Benign	1.0	P;P;P;P;P;P;P
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.84	N;N;N;N;N;N
REVEL	Benign	0.060
Sift	Benign	0.51	T;T;T;D;D;T
Sift4G	Benign	0.26	T;T;T;T;T;T
Polyphen		1.0	.;D;D;.;.;D
Vest4		0.26
MPC		0.034
ClinPred		0.020	T
GERP RS		3.5
Varity_R		0.20
gMVP		0.015

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: rs6940; hg19: chr1-159024668; COSMIC: COSV55534786;