chr10-89306703-T-G

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP7

The NM_001547.5(IFIT2):​c.747T>G​(p.Val249Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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: not found (cov: 32)
• 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 Submitted by: ClinGen
• lysosomal acid lipase deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Myriad Women’s Health, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• cholesteryl ester storage disease

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Wolman disease

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP7: Synonymous conserved (PhyloP=-0.533 with no splicing effect.

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.747T>G	p.Val249Val	synonymous	Exon 2 of 2	NP_001538.4
	LIPA	NM_001440836.1		c.131+7840A>C		intron	N/A	NP_001427765.1
	LIPA	NM_001440838.1		c.14+35858A>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.747T>G	p.Val249Val	synonymous	Exon 2 of 2	ENSP00000360891.3	P09913
	LIPA	ENST00000487618.5	TSL:1	n.181+7840A>C		intron	N/A
	IFIT2	ENST00000638108.1	TSL:5	c.747T>G	p.Val249Val	synonymous	Exon 5 of 5	ENSP00000490935.1	P09913

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 55

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.44
DANN	Benign	0.61
PhyloP100		-0.53

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;