14-94111759-T-C

Position:

• chr14-94111759-T-C

Variant summary

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

The NM_001130080.3(IFI27):​c.77T>C​(p.Val26Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,590 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: IFI27 NM_001130080.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.558

Genes affected

IFI27 (HGNC:5397): (interferon alpha inducible protein 27) Enables RNA polymerase II-specific DNA-binding transcription factor binding activity; identical protein binding activity; and lamin binding activity. Involved in several processes, including cellular protein metabolic process; defense response to other organism; and extrinsic apoptotic signaling pathway. Acts upstream of or within negative regulation of transcription by RNA polymerase II and regulation of protein export from nucleus. Located in mitochondrial membrane and nuclear inner membrane. [provided by Alliance of Genome Resources, Apr 2022]

IFI27 (HGNC:):

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=0.06543398).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IFI27	NM_001130080.3	c.77T>C	p.Val26Ala	missense_variant	2/5		NP_001123552.1
IFI27	NM_001288952.2	c.77T>C	p.Val26Ala	missense_variant	3/6		NP_001275881.1
IFI27	NM_001288956.2	c.77T>C	p.Val26Ala	missense_variant	2/5		NP_001275885.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IFI27	ENST00000621160.5	c.77T>C	p.Val26Ala	missense_variant	2/5	1		ENSP00000483498.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461590 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 727124

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: 0.00000360

Gnomad4 OTH exome AF: 0.00

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

Jun 30, 2024

The c.77T>C (p.V26A) alteration is located in exon 2 (coding exon 1) of the IFI27 gene. This alteration results from a T to C substitution at nucleotide position 77, causing the valine (V) at amino acid position 26 to be replaced by an alanine (A). 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	0.075
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	3.2
DANN	Benign	0.30
DEOGEN2	Benign	0.0056	T;T;.;.;T;T;.;T;T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.035	N
LIST_S2	Benign	0.34	T;T;.;T;.;T;T;.;T
M_CAP	Benign	0.0012	T
MetaRNN	Benign	0.065	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	.;N;.;.;N;.;.;N;.
PrimateAI	Benign	0.40	T
PROVEAN	Uncertain	-4.0	.;.;.;.;.;D;.;.;.
REVEL	Benign	0.080
Sift4G	Benign	0.48	T;T;T;T;T;D;T;T;T
Polyphen		0.0010	.;B;.;.;B;.;.;B;.
Vest4		0.13, 0.13, 0.11, 0.13, 0.10
MutPred		0.29		Loss of catalytic residue at V26 (P = 0.0098);Loss of catalytic residue at V26 (P = 0.0098);Loss of catalytic residue at V26 (P = 0.0098);Loss of catalytic residue at V26 (P = 0.0098);Loss of catalytic residue at V26 (P = 0.0098);Loss of catalytic residue at V26 (P = 0.0098);Loss of catalytic residue at V26 (P = 0.0098);Loss of catalytic residue at V26 (P = 0.0098);Loss of catalytic residue at V26 (P = 0.0098);
MVP		0.12
ClinPred		0.079	T
GERP RS		0.75
Varity_R		0.018
gMVP		0.16

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: rs1887196612; hg19: chr14-94578105;