10-89402282-A-G

Variant names:

• chr10-89402282-A-G
• rs759099907
• NM_001548.5:c.7A>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001270928.2(IFIT1):​c.-87A>G variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000069 in 1,449,184 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: IFIT1 NM_001270928.2 5_prime_UTR_premature_start_codon_gain
• Scores: Splicing: ADA: 0.00005671
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.62
• Publications: 1 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 Submitted by: ClinGen
• lysosomal acid lipase deficiency

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

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

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.037576705).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001270928.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IFIT1	NM_001548.5	MANE Select	c.7A>G	p.Thr3Ala	missense splice_region	Exon 2 of 2	NP_001539.3	P09914-1
	IFIT1	NM_001270928.2		c.-87A>G		5_prime_UTR_premature_start_codon_gain	Exon 3 of 3	NP_001257857.1	P09914-2
	IFIT1	NM_001270929.2		c.-87A>G		5_prime_UTR_premature_start_codon_gain	Exon 3 of 3	NP_001257858.1	P09914-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IFIT1	ENST00000371804.4	TSL:1 MANE Select	c.7A>G	p.Thr3Ala	missense splice_region	Exon 2 of 2	ENSP00000360869.3	P09914-1
	IFIT1	ENST00000546318.2	TSL:3	c.-87A>G		splice_region	Exon 3 of 3	ENSP00000441968.1	P09914-2
	IFIT1	ENST00000546318.2	TSL:3	c.-87A>G		5_prime_UTR	Exon 3 of 3	ENSP00000441968.1	P09914-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000411 AC: 1 AN: 243458 AF XY: 0.00000760

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000904

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.90e-7 AC: 1 AN: 1449184 Hom.: 0 Cov.: 28 AF XY: 0.00000139 AC XY: 1 AN XY: 720908

African (AFR) AF: 0.00 AC: 0 AN: 32946

American (AMR) AF: 0.00 AC: 0 AN: 43310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25400

East Asian (EAS) AF: 0.00 AC: 0 AN: 39622

South Asian (SAS) AF: 0.00 AC: 0 AN: 84742

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53076

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5712

European-Non Finnish (NFE) AF: 9.05e-7 AC: 1 AN: 1104468

Other (OTH) AF: 0.00 AC: 0 AN: 59908

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.062
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.79
CADD	Benign	0.0040
DANN	Benign	0.58
DEOGEN2	Benign	0.043	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.0065	N
LIST_S2	Benign	0.26	T
M_CAP	Benign	0.0048	T
MetaRNN	Benign	0.038	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.34	N
PhyloP100		-1.6
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.060	N
REVEL	Benign	0.0080
Sift	Benign	0.23	T
Sift4G	Benign	0.64	T
Polyphen		0.0090	B
Vest4		0.098
MutPred		0.16		Loss of phosphorylation at T3 (P = 0.0531)
MVP		0.15
MPC		0.064
ClinPred		0.034	T
GERP RS		-7.0
Varity_R		0.017
gMVP		0.082
Mutation Taster		=97/3	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000057
dbscSNV1_RF	Benign	0.026
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: rs759099907; hg19: chr10-91162039; COSMIC: COSV100878683;