rs1727

Positions:

• chr10-89307012-C-A
• chr10-89307012-C-G
• chr10-89307012-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

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. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.82 (52344 hom., cov: 30)
  • Exomes 𝑓: 0.76 (423086 hom.)
• Consequence: IFIT2 NM_001547.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.871

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]

ACMG classification

Verdict is Benign. Variant got -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/exons	MANE	UniProt
IFIT2	NM_001547.5	c.1056C>A	p.Asp352Glu	missense_variant	2/2	ENST00000371826.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IFIT2	ENST00000371826.4	c.1056C>A	p.Asp352Glu	missense_variant	2/2	1	NM_001547.5	P1

Frequencies

GnomAD3 genomes AF: 0.824 AC: 125231 AN: 152004 Hom.: 52295 Cov.: 30

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

GnomAD3 exomes AF: 0.795 AC: 198067 AN: 249018 Hom.: 79705 AF XY: 0.796 AC XY: 107469 AN XY: 135076

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 SAS exome AF: 0.846

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.: 49 AF XY: 0.761 AC XY: 553167 AN XY: 727102

Gnomad4 AFR exome AF: 0.961

Gnomad4 AMR exome AF: 0.720

Gnomad4 ASJ exome AF: 0.797

Gnomad4 EAS exome AF: 0.982

Gnomad4 SAS exome AF: 0.842

Gnomad4 FIN exome AF: 0.804

Gnomad4 NFE exome AF: 0.735

Gnomad4 OTH exome AF: 0.778

GnomAD4 genome AF: 0.824 AC: 125330 AN: 152122 Hom.: 52344 Cov.: 30 AF XY: 0.828 AC XY: 61565 AN XY: 74352

Gnomad4 AFR AF: 0.951

Gnomad4 AMR AF: 0.764

Gnomad4 ASJ AF: 0.799

Gnomad4 EAS AF: 0.987

Gnomad4 SAS AF: 0.851

Gnomad4 FIN AF: 0.818

Gnomad4 NFE AF: 0.748

Gnomad4 OTH AF: 0.815

Alfa AF: 0.766 Hom.: 104505

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	T
BayesDel_noAF	Benign	-0.73
CADD	Benign	6.3
DANN	Benign	0.82
DEOGEN2	Benign	0.019	T;T;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-0.92
FATHMM_MKL	Benign	0.067	N
MetaRNN	Benign	9.0e-7	T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	-2.2	N;N;.
MutationTaster	Benign	1.1e-15	P;P;P;P;P
PrimateAI	Benign	0.27	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	T
GERP RS		2.2
Varity_R		0.029
gMVP		0.072

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: rs1727; hg19: chr10-91066769;