rs954439

Variant names:

• chr10-89306703-T-A
• rs954439
• NM_001547.5:c.747T>A

Your query was ambiguous. Multiple possible variants found:

• chr10-89306703-T-A
• chr10-89306703-T-C
• chr10-89306703-T-G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP7 BA1

The NM_001547.5(IFIT2):​c.747T>A​(p.Val249Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.508 in 1,613,766 control chromosomes in the GnomAD database, including 216,205 homozygotes. 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: 𝑓 0.60 (29313 hom., cov: 32)
  • Exomes 𝑓: 0.50 (186892 hom.)
• Consequence: IFIT2 NM_001547.5 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.533
• Publications: 29 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP7: Synonymous conserved (PhyloP=-0.533 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.843 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IFIT2	NM_001547.5	c.747T>A	p.Val249Val	synonymous_variant	Exon 2 of 2	ENST00000371826.4	NP_001538.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IFIT2	ENST00000371826.4	c.747T>A	p.Val249Val	synonymous_variant	Exon 2 of 2	1	NM_001547.5	ENSP00000360891.3

Frequencies

GnomAD3 genomes AF: 0.600 AC: 91134 AN: 151984 Hom.: 29277 Cov.: 32

Gnomad AFR AF: 0.825

Gnomad AMI AF: 0.621

Gnomad AMR AF: 0.555

Gnomad ASJ AF: 0.570

Gnomad EAS AF: 0.864

Gnomad SAS AF: 0.554

Gnomad FIN AF: 0.464

Gnomad MID AF: 0.528

Gnomad NFE AF: 0.478

Gnomad OTH AF: 0.599

GnomAD2 exomes AF: 0.552 AC: 137605 AN: 249424 AF XY: 0.544

Gnomad AFR exome AF: 0.836

Gnomad AMR exome AF: 0.536

Gnomad ASJ exome AF: 0.557

Gnomad EAS exome AF: 0.877

Gnomad FIN exome AF: 0.464

Gnomad NFE exome AF: 0.484

Gnomad OTH exome AF: 0.543

GnomAD4 exome AF: 0.498 AC: 727884 AN: 1461664 Hom.: 186892 Cov.: 55 AF XY: 0.498 AC XY: 362339 AN XY: 727140

African (AFR) AF: 0.837 AC: 28024 AN: 33466

American (AMR) AF: 0.536 AC: 23984 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.565 AC: 14768 AN: 26132

East Asian (EAS) AF: 0.843 AC: 33474 AN: 39698

South Asian (SAS) AF: 0.543 AC: 46809 AN: 86240

European-Finnish (FIN) AF: 0.469 AC: 25074 AN: 53420

Middle Eastern (MID) AF: 0.553 AC: 3191 AN: 5768

European-Non Finnish (NFE) AF: 0.468 AC: 520466 AN: 1111840

Other (OTH) AF: 0.532 AC: 32094 AN: 60382

GnomAD4 genome AF: 0.600 AC: 91218 AN: 152102 Hom.: 29313 Cov.: 32 AF XY: 0.600 AC XY: 44620 AN XY: 74372

African (AFR) AF: 0.825 AC: 34247 AN: 41518

American (AMR) AF: 0.554 AC: 8465 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.570 AC: 1980 AN: 3472

East Asian (EAS) AF: 0.864 AC: 4476 AN: 5178

South Asian (SAS) AF: 0.554 AC: 2666 AN: 4816

European-Finnish (FIN) AF: 0.464 AC: 4909 AN: 10590

Middle Eastern (MID) AF: 0.514 AC: 151 AN: 294

European-Non Finnish (NFE) AF: 0.478 AC: 32488 AN: 67938

Other (OTH) AF: 0.602 AC: 1271 AN: 2112

Alfa AF: 0.514 Hom.: 6850

Bravo AF: 0.615

Asia WGS AF: 0.698 AC: 2423 AN: 3478

EpiCase AF: 0.491

EpiControl AF: 0.484

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.42
DANN	Benign	0.84
PhyloP100		-0.53
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs954439; hg19: chr10-91066460; COSMIC: COSV108040327;