chr1-78635392-T-G

Position:

• chr1-78635392-T-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_006820.4(IFI44L):​c.779T>G​(p.Leu260Trp) variant causes a missense change. The variant allele was found at a frequency of 0.0000197 in 152,166 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: 𝑓 0.000020 (0 hom., cov: 32)
• Consequence: IFI44L NM_006820.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.53

Genes affected

IFI44L (HGNC:17817): (interferon induced protein 44 like) Predicted to enable GTP binding activity. Involved in defense response to virus. Predicted to be located in cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.949

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IFI44L	NM_006820.4	c.779T>G	p.Leu260Trp	missense_variant	5/9	ENST00000370751.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IFI44L	ENST00000370751.10	c.779T>G	p.Leu260Trp	missense_variant	5/9	1	NM_006820.4	P1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152166 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000478

GnomAD4 exome Cov.: 29

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152166 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74336

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.0000282 Hom.: 0

Bravo AF: 0.0000113

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

Dec 18, 2023

The c.779T>G (p.L260W) alteration is located in exon 5 (coding exon 4) of the IFI44L gene. This alteration results from a T to G substitution at nucleotide position 779, causing the leucine (L) at amino acid position 260 to be replaced by a tryptophan (W). 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	Uncertain	0.51
BayesDel_addAF	Uncertain	0.073	D
BayesDel_noAF	Benign	-0.13
CADD	Uncertain	26
DANN	Benign	0.96
DEOGEN2	Benign	0.15	T
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.74	T
M_CAP	Benign	0.018	T
MetaRNN	Pathogenic	0.95	D
MetaSVM	Benign	-0.48	T
MutationAssessor	Pathogenic	3.2	M
MutationTaster	Benign	0.80	D;D
PrimateAI	Uncertain	0.62	T
PROVEAN	Pathogenic	-5.6	D
REVEL	Uncertain	0.36
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.75
MutPred		0.83		Loss of sheet (P = 0.1158);
MVP		0.34
MPC		0.10
ClinPred		0.99	D
GERP RS		4.5
Varity_R		0.78
gMVP		0.74

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs1434616567; hg19: chr1-79101077;