10-89402318-G-C

Position:

• chr10-89402318-G-C

Variant summary

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

The NM_001548.5(IFIT1):​c.43G>C​(p.Glu15Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000281 in 1,613,764 control chromosomes in the GnomAD database, including 1 homozygotes. 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: 𝑓 0.00024 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00029 (1 hom.)
• Consequence: IFIT1 NM_001548.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.302

Genes affected

IFIT1 (HGNC:5407): (interferon induced protein with tetratricopeptide repeats 1) This gene encodes a protein containing tetratricopeptide repeats that was originally identified as induced upon treatment with interferon. The encoded protein may inhibit viral replication and translational initiation. This gene is located in a cluster on chromosome 10 with five other closely related genes. There is a pseudogene for this gene on chromosome 13. Alternatively spliced transcript variants encoding multiple isoforms have been observed. [provided by RefSeq, Aug 2012]

LIPA (HGNC:6617): (lipase A, lysosomal acid type) This gene encodes lipase A, the lysosomal acid lipase (also known as cholesterol ester hydrolase). This enzyme functions in the lysosome to catalyze the hydrolysis of cholesteryl esters and triglycerides. Mutations in this gene can result in Wolman disease and cholesteryl ester storage disease. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Jan 2014]

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=0.009900391).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IFIT1	NM_001548.5	c.43G>C	p.Glu15Gln	missense_variant	2/2	ENST00000371804.4	NP_001539.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IFIT1	ENST00000371804.4	c.43G>C	p.Glu15Gln	missense_variant	2/2	1	NM_001548.5	ENSP00000360869.3
IFIT1	ENST00000546318	c.-51G>C		5_prime_UTR_variant	3/3	3		ENSP00000441968.1
LIPA	ENST00000371837.5	c.61+10473C>G		intron_variant		2		ENSP00000360903.1

Frequencies

GnomAD3 genomes AF: 0.000237 AC: 36 AN: 152148 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00104

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000323

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000307 AC: 77 AN: 250992 Hom.: 0 AF XY: 0.000332 AC XY: 45 AN XY: 135652

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000299

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00153

Gnomad NFE exome AF: 0.000361

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000286 AC: 418 AN: 1461498 Hom.: 1 Cov.: 30 AF XY: 0.000290 AC XY: 211 AN XY: 727068

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00127

Gnomad4 NFE exome AF: 0.000293

Gnomad4 OTH exome AF: 0.000199

GnomAD4 genome AF: 0.000236 AC: 36 AN: 152266 Hom.: 0 Cov.: 32 AF XY: 0.000269 AC XY: 20 AN XY: 74446

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00104

Gnomad4 NFE AF: 0.000323

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000410 Hom.: 0

Bravo AF: 0.000159

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000222 AC: 27

EpiCase AF: 0.000600

EpiControl AF: 0.000415

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 13, 2023

The c.43G>C (p.E15Q) alteration is located in exon 2 (coding exon 2) of the IFIT1 gene. This alteration results from a G to C substitution at nucleotide position 43, causing the glutamic acid (E) at amino acid position 15 to be replaced by a glutamine (Q). 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	-0.58	T
BayesDel_noAF	Benign	-0.74
CADD	Benign	3.1
DANN	Benign	0.64
DEOGEN2	Benign	0.049	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.026	N
LIST_S2	Benign	0.021	T
M_CAP	Benign	0.0068	T
MetaRNN	Benign	0.0099	T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	-0.14	N
PrimateAI	Benign	0.24	T
PROVEAN	Benign	0.13	N
REVEL	Benign	0.056
Sift	Benign	0.59	T
Sift4G	Benign	0.59	T
Polyphen		0.0080	B
Vest4		0.046
MVP		0.21
MPC		0.066
ClinPred		0.018	T
GERP RS		-1.8
Varity_R		0.18
gMVP		0.064

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: rs181412791; hg19: chr10-91162075;