rs2070845

Variant names:

• chr10-89306318-A-G
• rs2070845
• NM_001547.5:c.362A>G

Variant summary

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

The NM_001547.5(IFIT2):​c.362A>G​(p.Lys121Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.23 in 1,613,760 control chromosomes in the GnomAD database, including 44,174 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.24 (4501 hom., cov: 32)
  • Exomes 𝑓: 0.23 (39673 hom.)
• Consequence: IFIT2 NM_001547.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.88
• Publications: 36 publications found

Genes affected

IFIT2 (HGNC:5409): (interferon induced protein with tetratricopeptide repeats 2) Enables RNA binding activity. Involved in negative regulation of protein binding activity; positive regulation of apoptotic process; and response to virus. Located in endoplasmic reticulum. [provided by Alliance of Genome Resources, Apr 2022]

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 (MetaRNN=0.0033346713).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.262 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001547.5. 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
	IFIT2	NM_001547.5	MANE Select	c.362A>G	p.Lys121Arg	missense	Exon 2 of 2	NP_001538.4
	LIPA	NM_001440836.1		c.131+8225T>C		intron	N/A	NP_001427765.1
	LIPA	NM_001440838.1		c.14+36243T>C		intron	N/A	NP_001427767.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IFIT2	ENST00000371826.4	TSL:1 MANE Select	c.362A>G	p.Lys121Arg	missense	Exon 2 of 2	ENSP00000360891.3
	LIPA	ENST00000487618.5	TSL:1	n.181+8225T>C		intron	N/A
	IFIT2	ENST00000638108.1	TSL:5	c.362A>G	p.Lys121Arg	missense	Exon 5 of 5	ENSP00000490935.1

Frequencies

GnomAD3 genomes AF: 0.239 AC: 36334 AN: 151962 Hom.: 4501 Cov.: 32

Gnomad AFR AF: 0.266

Gnomad AMI AF: 0.379

Gnomad AMR AF: 0.239

Gnomad ASJ AF: 0.270

Gnomad EAS AF: 0.129

Gnomad SAS AF: 0.120

Gnomad FIN AF: 0.187

Gnomad MID AF: 0.250

Gnomad NFE AF: 0.244

Gnomad OTH AF: 0.252

GnomAD2 exomes AF: 0.212 AC: 52847 AN: 249812 AF XY: 0.207

Gnomad AFR exome AF: 0.267

Gnomad AMR exome AF: 0.196

Gnomad ASJ exome AF: 0.266

Gnomad EAS exome AF: 0.121

Gnomad FIN exome AF: 0.198

Gnomad NFE exome AF: 0.246

Gnomad OTH exome AF: 0.235

GnomAD4 exome AF: 0.229 AC: 335431 AN: 1461680 Hom.: 39673 Cov.: 35 AF XY: 0.226 AC XY: 164273 AN XY: 727154

African (AFR) AF: 0.259 AC: 8672 AN: 33472

American (AMR) AF: 0.198 AC: 8858 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.266 AC: 6944 AN: 26132

East Asian (EAS) AF: 0.157 AC: 6217 AN: 39698

South Asian (SAS) AF: 0.116 AC: 10026 AN: 86258

European-Finnish (FIN) AF: 0.204 AC: 10897 AN: 53398

Middle Eastern (MID) AF: 0.245 AC: 1414 AN: 5768

European-Non Finnish (NFE) AF: 0.242 AC: 268566 AN: 1111840

Other (OTH) AF: 0.229 AC: 13837 AN: 60394

GnomAD4 genome AF: 0.239 AC: 36343 AN: 152080 Hom.: 4501 Cov.: 32 AF XY: 0.234 AC XY: 17412 AN XY: 74346

African (AFR) AF: 0.266 AC: 11019 AN: 41478

American (AMR) AF: 0.238 AC: 3641 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.270 AC: 937 AN: 3472

East Asian (EAS) AF: 0.128 AC: 663 AN: 5168

South Asian (SAS) AF: 0.119 AC: 574 AN: 4824

European-Finnish (FIN) AF: 0.187 AC: 1983 AN: 10578

Middle Eastern (MID) AF: 0.241 AC: 71 AN: 294

European-Non Finnish (NFE) AF: 0.244 AC: 16579 AN: 67968

Other (OTH) AF: 0.252 AC: 532 AN: 2110

Alfa AF: 0.242 Hom.: 18529

Bravo AF: 0.246

TwinsUK AF: 0.232 AC: 861

ALSPAC AF: 0.239 AC: 921

ESP6500AA AF: 0.251 AC: 1062

ESP6500EA AF: 0.242 AC: 2063

ExAC AF: 0.214 AC: 25933

Asia WGS AF: 0.140 AC: 485 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	5.6
DANN	Benign	0.79
DEOGEN2	Benign	0.033	T
Eigen	Benign	-0.81
Eigen_PC	Benign	-0.75
FATHMM_MKL	Benign	0.65	D
LIST_S2	Benign	0.46	T
MetaRNN	Benign	0.0033	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.70	N
PhyloP100		1.9
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.085
Sift	Benign	0.37	T
Sift4G	Benign	0.58	T
Polyphen		0.028	B
Vest4		0.024
MPC		0.15
ClinPred		0.00058	T
GERP RS		2.2
PromoterAI		0.0054	Neutral
Varity_R		0.081
gMVP		0.11
Mutation Taster		=95/5	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs2070845; hg19: chr10-91066075; COSMIC: COSV51079081;