1-27668351-G-A

Variant names:

• chr1-27668351-G-A
• rs2090368987
• NM_002038.4:c.173C>T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_002038.4(IFI6):​c.173C>T​(p.Ala58Val) 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. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: IFI6 NM_002038.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.224

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.34273526).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IFI6	NM_002038.4	c.173C>T	p.Ala58Val	missense_variant	Exon 4 of 5	ENST00000361157.11	NP_002029.3
IFI6	NM_022873.3	c.197C>T	p.Ala66Val	missense_variant	Exon 4 of 5		NP_075011.1
IFI6	NM_022872.3	c.185C>T	p.Ala62Val	missense_variant	Exon 4 of 5		NP_075010.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IFI6	ENST00000361157.11	c.173C>T	p.Ala58Val	missense_variant	Exon 4 of 5	1	NM_002038.4	ENSP00000354736.6
IFI6	ENST00000362020.4	c.185C>T	p.Ala62Val	missense_variant	Exon 4 of 5	1		ENSP00000355152.4
IFI6	ENST00000339145.8	c.197C>T	p.Ala66Val	missense_variant	Exon 4 of 5	2		ENSP00000342513.4
IFI6	ENST00000679644.1	c.173C>T	p.Ala58Val	missense_variant	Exon 4 of 5			ENSP00000505325.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 20, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.197C>T (p.A66V) alteration is located in exon 4 (coding exon 3) of the IFI6 gene. This alteration results from a C to T substitution at nucleotide position 197, causing the alanine (A) at amino acid position 66 to be replaced by a valine (V). 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	0.073
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	12
DANN	Uncertain	0.98
DEOGEN2	Benign	0.16	T;.;.
Eigen	Benign	-0.77
Eigen_PC	Benign	-0.89
FATHMM_MKL	Benign	0.037	N
LIST_S2	Benign	0.66	T;T;T
M_CAP	Benign	0.0051	T
MetaRNN	Benign	0.34	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.8	L;.;.
PrimateAI	Benign	0.44	T
PROVEAN	Uncertain	-2.5	N;N;N
REVEL	Benign	0.050
Sift	Benign	0.14	T;T;T
Sift4G	Benign	0.099	T;T;T
Polyphen		0.095	B;P;.
Vest4		0.20
MutPred		0.76		Loss of helix (P = 0.3949);.;.;
MVP		0.17
MPC		0.69
ClinPred		0.093	T
GERP RS		0.52
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.041
gMVP		0.48

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: rs2090368987; hg19: chr1-27994862;