chr10-89417633-G-A

Position:

• chr10-89417633-G-A

Variant summary

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

The NM_012420.3(IFIT5):​c.434G>A​(p.Gly145Asp) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: IFIT5 NM_012420.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.84

Genes affected

IFIT5 (HGNC:13328): (interferon induced protein with tetratricopeptide repeats 5) Enables nucleic acid binding activity. Involved in defense response to virus; negative regulation of viral genome replication; and positive regulation of I-kappaB kinase/NF-kappaB signaling. Located in actin cytoskeleton; apical part of cell; and ruffle membrane. Colocalizes with IkappaB kinase complex. [provided by Alliance of Genome Resources, Apr 2022]

LOC107984251 (HGNC:):

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, 0.965

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IFIT5	NM_012420.3	c.434G>A	p.Gly145Asp	missense_variant	2/2	ENST00000371795.5	NP_036552.1
LOC107984251	XR_001747541.2	n.74-1828C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IFIT5	ENST00000371795.5	c.434G>A	p.Gly145Asp	missense_variant	2/2	1	NM_012420.3	ENSP00000360860	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

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

Feb 28, 2024

The c.434G>A (p.G145D) alteration is located in exon 2 (coding exon 2) of the IFIT5 gene. This alteration results from a G to A substitution at nucleotide position 434, causing the glycine (G) at amino acid position 145 to be replaced by an aspartic acid (D). 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	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.19
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.51	D
Eigen	Pathogenic	0.95
Eigen_PC	Pathogenic	0.91
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.97	D
M_CAP	Benign	0.043	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Uncertain	0.13	D
MutationAssessor	Pathogenic	3.1	M
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.55	T
PROVEAN	Pathogenic	-6.9	D
REVEL	Uncertain	0.55
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.85
MutPred		0.88		Loss of MoRF binding (P = 0.0659);
MVP		0.86
MPC		0.77
ClinPred		0.99	D
GERP RS		6.0
Varity_R		0.93
gMVP		0.83

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: rs758474945; hg19: chr10-91177390;