1-27666399-A-C

Position:

• chr1-27666399-A-C

Variant summary

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

The ENST00000361157.11(IFI6):​c.375T>G​(p.Ser125Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000753 in 1,460,944 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.0000075 (0 hom.)
• Consequence: IFI6 ENST00000361157.11 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.127

Genes affected

IFI6 (HGNC:4054): (interferon alpha inducible protein 6) This gene was first identified as one of the many genes induced by interferon. The encoded protein may play a critical role in the regulation of apoptosis. A minisatellite that consists of 26 repeats of a 12 nucleotide repeating element resembling the mammalian splice donor consensus sequence begins near the end of the second exon. Alternatively spliced transcript variants that encode different isoforms by using the two downstream repeat units as splice donor sites have been described. [provided by RefSeq, Jul 2008]

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=0.07013026).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IFI6	NM_002038.4	c.375T>G	p.Ser125Arg	missense_variant	5/5	ENST00000361157.11	NP_002029.3
IFI6	NM_022873.3	c.399T>G	p.Ser133Arg	missense_variant	5/5		NP_075011.1
IFI6	NM_022872.3	c.387T>G	p.Ser129Arg	missense_variant	5/5		NP_075010.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IFI6	ENST00000361157.11	c.375T>G	p.Ser125Arg	missense_variant	5/5	1	NM_002038.4	ENSP00000354736	A2
IFI6	ENST00000362020.4	c.387T>G	p.Ser129Arg	missense_variant	5/5	1		ENSP00000355152	P4
IFI6	ENST00000339145.8	c.399T>G	p.Ser133Arg	missense_variant	5/5	2		ENSP00000342513	A2
IFI6	ENST00000679644.1	c.375T>G	p.Ser125Arg	missense_variant	5/5			ENSP00000505325	A2

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 0.00000753 AC: 11 AN: 1460944 Hom.: 0 Cov.: 31 AF XY: 0.00000688 AC XY: 5 AN XY: 726858

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: 0.00000990

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 30

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

Sep 20, 2023

The c.399T>G (p.S133R) alteration is located in exon 5 (coding exon 4) of the IFI6 gene. This alteration results from a T to G substitution at nucleotide position 399, causing the serine (S) at amino acid position 133 to be replaced by an arginine (R). 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	0.13
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	5.5
DANN	Benign	0.95
DEOGEN2	Benign	0.10	T;.;.
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.043	N
LIST_S2	Benign	0.44	T;T;T
M_CAP	Benign	0.0098	T
MetaRNN	Benign	0.070	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.5	L;.;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.97	N;N;N
REVEL	Benign	0.034
Sift	Uncertain	0.0040	D;D;D
Sift4G	Uncertain	0.052	T;D;T
Polyphen		0.27	B;P;.
Vest4		0.080
MutPred		0.12		Loss of phosphorylation at S125 (P = 0.0392);.;.;
MVP		0.15
MPC		0.94
ClinPred		0.11	T
GERP RS		-1.2
Varity_R		0.057
gMVP		0.30

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: chr1-27992910;