rs17468739

Positions:

• chr10-89306192-A-C
• chr10-89306192-A-G
• chr10-89306192-A-T

Variant summary

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

The NM_001547.5(IFIT2):​c.236A>C​(p.Glu79Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.143 in 1,614,066 control chromosomes in the GnomAD database, including 18,962 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 0.11 (1290 hom., cov: 32)
  • Exomes 𝑓: 0.15 (17672 hom.)
• Consequence: IFIT2 NM_001547.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.508

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=0.0018186569).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.167 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IFIT2	NM_001547.5	c.236A>C	p.Glu79Ala	missense_variant	2/2	ENST00000371826.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IFIT2	ENST00000371826.4	c.236A>C	p.Glu79Ala	missense_variant	2/2	1	NM_001547.5	P1

Frequencies

GnomAD3 genomes AF: 0.109 AC: 16597 AN: 152154 Hom.: 1291 Cov.: 32

Gnomad AFR AF: 0.0286

Gnomad AMI AF: 0.202

Gnomad AMR AF: 0.120

Gnomad ASJ AF: 0.220

Gnomad EAS AF: 0.00173

Gnomad SAS AF: 0.0356

Gnomad FIN AF: 0.0590

Gnomad MID AF: 0.133

Gnomad NFE AF: 0.169

Gnomad OTH AF: 0.130

GnomAD3 exomes AF: 0.112 AC: 28018 AN: 250506 Hom.: 2184 AF XY: 0.113 AC XY: 15270 AN XY: 135576

Gnomad AFR exome AF: 0.0257

Gnomad AMR exome AF: 0.0820

Gnomad ASJ exome AF: 0.213

Gnomad EAS exome AF: 0.000490

Gnomad SAS exome AF: 0.0372

Gnomad FIN exome AF: 0.0650

Gnomad NFE exome AF: 0.170

Gnomad OTH exome AF: 0.142

GnomAD4 exome AF: 0.147 AC: 214704 AN: 1461794 Hom.: 17672 Cov.: 34 AF XY: 0.144 AC XY: 104884 AN XY: 727204

Gnomad4 AFR exome AF: 0.0250

Gnomad4 AMR exome AF: 0.0872

Gnomad4 ASJ exome AF: 0.212

Gnomad4 EAS exome AF: 0.000277

Gnomad4 SAS exome AF: 0.0370

Gnomad4 FIN exome AF: 0.0702

Gnomad4 NFE exome AF: 0.169

Gnomad4 OTH exome AF: 0.137

GnomAD4 genome AF: 0.109 AC: 16587 AN: 152272 Hom.: 1290 Cov.: 32 AF XY: 0.103 AC XY: 7654 AN XY: 74458

Gnomad4 AFR AF: 0.0285

Gnomad4 AMR AF: 0.120

Gnomad4 ASJ AF: 0.220

Gnomad4 EAS AF: 0.00173

Gnomad4 SAS AF: 0.0350

Gnomad4 FIN AF: 0.0590

Gnomad4 NFE AF: 0.169

Gnomad4 OTH AF: 0.128

Alfa AF: 0.148 Hom.: 2459

Bravo AF: 0.112

TwinsUK AF: 0.163 AC: 605

ALSPAC AF: 0.163 AC: 628

ESP6500AA AF: 0.0361 AC: 159

ESP6500EA AF: 0.172 AC: 1483

ExAC AF: 0.112 AC: 13623

Asia WGS AF: 0.0230 AC: 78 AN: 3478

EpiCase AF: 0.180

EpiControl AF: 0.175

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	0.70
DANN	Benign	0.64
DEOGEN2	Benign	0.41	T;T;.
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.12	N
MetaRNN	Benign	0.0018	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.8	L;L;.
MutationTaster	Benign	0.32	P;P;P;P;P
PrimateAI	Benign	0.27	T
Polyphen		0.032	B;B;.
Vest4		0.071, 0.057
MPC		0.20
ClinPred		0.0077	T
GERP RS		-2.1
Varity_R		0.17
gMVP		0.32

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: rs17468739; hg19: chr10-91065949; COSMIC: COSV51080681;