10-89393942-T-C

Variant names:

• chr10-89393942-T-C
• rs303217
• NM_001548.5:c.5+1225T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001548.5(IFIT1):​c.5+1225T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.623 in 152,114 control chromosomes in the GnomAD database, including 31,947 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.62 (31947 hom., cov: 32)
• Consequence: IFIT1 NM_001548.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.519
• Publications: 5 publications found

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]

LIPA Gene-Disease associations (from GenCC):

• lysosomal acid lipase deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Genomics England PanelApp, ClinGen, Myriad Women’s Health, Labcorp Genetics (formerly Invitae)
• cholesteryl ester storage disease

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Wolman disease

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.0).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.874 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IFIT1	NM_001548.5	c.5+1225T>C		intron_variant	Intron 1 of 1	ENST00000371804.4	NP_001539.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IFIT1	ENST00000371804.4	c.5+1225T>C		intron_variant	Intron 1 of 1	1	NM_001548.5	ENSP00000360869.3
IFIT1	ENST00000546318.2	c.-89+601T>C		intron_variant	Intron 2 of 2	3		ENSP00000441968.1
LIPA	ENST00000371837.5	c.61+18849A>G		intron_variant	Intron 2 of 8	2		ENSP00000360903.1

Frequencies

GnomAD3 genomes AF: 0.622 AC: 94615 AN: 151996 Hom.: 31906 Cov.: 32

Gnomad AFR AF: 0.882

Gnomad AMI AF: 0.657

Gnomad AMR AF: 0.578

Gnomad ASJ AF: 0.610

Gnomad EAS AF: 0.848

Gnomad SAS AF: 0.541

Gnomad FIN AF: 0.496

Gnomad MID AF: 0.589

Gnomad NFE AF: 0.483

Gnomad OTH AF: 0.618

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.623 AC: 94704 AN: 152114 Hom.: 31947 Cov.: 32 AF XY: 0.624 AC XY: 46404 AN XY: 74370

African (AFR) AF: 0.882 AC: 36586 AN: 41496

American (AMR) AF: 0.578 AC: 8833 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.610 AC: 2117 AN: 3468

East Asian (EAS) AF: 0.848 AC: 4385 AN: 5174

South Asian (SAS) AF: 0.541 AC: 2608 AN: 4820

European-Finnish (FIN) AF: 0.496 AC: 5237 AN: 10552

Middle Eastern (MID) AF: 0.575 AC: 169 AN: 294

European-Non Finnish (NFE) AF: 0.483 AC: 32863 AN: 67994

Other (OTH) AF: 0.619 AC: 1308 AN: 2114

Alfa AF: 0.538 Hom.: 31810

Bravo AF: 0.640

Asia WGS AF: 0.679 AC: 2356 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	2.2
DANN	Benign	0.50
PhyloP100		-0.52
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs303217; hg19: chr10-91153699;