dbSNP rs1727: IFIT2:p.Asp352Glu (chr10-89307012-C-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_001547.5(IFIT2):c.1056C>A(p.Asp352Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.764 in 1,613,674 control chromosomes in the GnomAD database, including 475,430 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 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 0.82 ( 52344 hom., cov: 30)

Exomes 𝑓: 0.76 ( 423086 hom. )

Consequence

IFIT2
NM_001547.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.871

Publications

55 publications found

Variant links:

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]

IFIT2 links:

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

LIPA links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (MetaRNN=8.963274E-7).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.964 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IFIT2	NM_001547.5 link	c.1056C>A	p.Asp352Glu	missense_variant	Exon 2 of 2	ENST00000371826.4	NP_001538.4	P09913Q05DN2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IFIT2	ENST00000371826.4 link	c.1056C>A	p.Asp352Glu	missense_variant	Exon 2 of 2	1	NM_001547.5	ENSP00000360891.3		P09913

Frequencies

GnomAD3 genomes

AF:

0.824

AC:

125231

AN:

152004

Hom.:

52295

Cov.:

show subpopulations

Gnomad AFR

AF:

0.951

Gnomad AMI

AF:

0.787

Gnomad AMR

AF:

0.765

Gnomad ASJ

AF:

0.799

Gnomad EAS

AF:

0.987

Gnomad SAS

AF:

0.852

Gnomad FIN

AF:

0.818

Gnomad MID

AF:

0.782

Gnomad NFE

AF:

0.748

Gnomad OTH

AF:

0.813

GnomAD2 exomes

AF:

0.795

AC:

198067

AN:

249018

AF XY:

0.796

show subpopulations

Gnomad AFR exome

AF:

0.957

Gnomad AMR exome

AF:

0.715

Gnomad ASJ exome

AF:

0.794

Gnomad EAS exome

AF:

0.990

Gnomad FIN exome

AF:

0.807

Gnomad NFE exome

AF:

0.751

Gnomad OTH exome

AF:

0.789

GnomAD4 exome

AF:

0.758

AC:

1108149

AN:

1461552

Hom.:

423086

Cov.:

AF XY:

0.761

AC XY:

553167

AN XY:

727102

show subpopulations

African (AFR)

AF:

0.961

AC:

32187

AN:

33476

American (AMR)

AF:

0.720

AC:

32192

AN:

44702

Ashkenazi Jewish (ASJ)

AF:

0.797

AC:

20836

AN:

26132

East Asian (EAS)

AF:

0.982

AC:

38992

AN:

39688

South Asian (SAS)

AF:

0.842

AC:

72655

AN:

86252

European-Finnish (FIN)

AF:

0.804

AC:

42948

AN:

53394

Middle Eastern (MID)

AF:

0.805

AC:

4645

AN:

5768

European-Non Finnish (NFE)

AF:

0.735

AC:

816740

AN:

1111754

Other (OTH)

AF:

0.778

AC:

46954

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

14870

29740

44611

59481

74351

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.824

AC:

125330

AN:

152122

Hom.:

52344

Cov.:

AF XY:

0.828

AC XY:

61565

AN XY:

74352

show subpopulations

African (AFR)

AF:

0.951

AC:

39475

AN:

41502

American (AMR)

AF:

0.764

AC:

11664

AN:

15270

Ashkenazi Jewish (ASJ)

AF:

0.799

AC:

2774

AN:

3470

East Asian (EAS)

AF:

0.987

AC:

5099

AN:

5168

South Asian (SAS)

AF:

0.851

AC:

4105

AN:

4822

European-Finnish (FIN)

AF:

0.818

AC:

8661

AN:

10582

Middle Eastern (MID)

AF:

0.776

AC:

228

AN:

294

European-Non Finnish (NFE)

AF:

0.748

AC:

50883

AN:

67988

Other (OTH)

AF:

0.815

AC:

1723

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1055

2109

3164

4218

5273

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.772

Hom.:

200767

Bravo

AF:

0.820

TwinsUK

AF:

0.734

AC:

2722

ALSPAC

AF:

0.738

AC:

2843

ESP6500AA

AF:

0.949

AC:

3657

ESP6500EA

AF:

0.748

AC:

6190

ExAC

AF:

0.801

AC:

96762

Asia WGS

AF:

0.909

AC:

3158

AN:

3478

EpiCase

AF:

0.751

EpiControl

AF:

0.748

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.083

BayesDel_addAF

Benign

-0.77

BayesDel_noAF

Benign

-0.73

CADD

Benign

6.3

(source)

DANN

Benign

0.82

DEOGEN2

Benign

0.019

T;T;.

Eigen

Benign

-1.2

Eigen_PC

Benign

-0.92

FATHMM_MKL

Benign

0.067

LIST_S2

Benign

0.048

.;T;T

MetaRNN

Benign

9.0e-7

T;T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

-2.2

N;N;.

PhyloP100

0.87

PrimateAI

Benign

0.27

PROVEAN

Benign

1.9

.;N;.

REVEL

Benign

0.033

Sift

Benign

0.98

.;T;.

Sift4G

Benign

1.0

.;T;T

Polyphen

0.0

B;B;.

Vest4

0.016, 0.015

MutPred

0.32

Gain of disorder (P = 0.1214);Gain of disorder (P = 0.1214);Gain of disorder (P = 0.1214);

MPC

0.16

ClinPred

0.0035

GERP RS

2.2

Varity_R

0.029

gMVP

0.072

Mutation Taster

=99/1

polymorphism (auto)

(source)

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

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rs1727

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over