10-89402920-C-T

Variant names:

• chr10-89402920-C-T
• rs303210
• NM_001548.5:c.645C>T

Variant summary

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

The NM_001548.5(IFIT1):​c.645C>T​(p.Asp215Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.204 in 1,613,896 control chromosomes in the GnomAD database, including 37,572 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 0.17 (2974 hom., cov: 33)
  • Exomes 𝑓: 0.21 (34598 hom.)
• Consequence: IFIT1 NM_001548.5 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.82
• Publications: 23 publications found

Genes affected

IFIT1 (HGNC:5407): (interferon induced protein with tetratricopeptide repeats 1) This gene encodes a protein containing tetratricopeptide repeats that was originally identified as induced upon treatment with interferon. The encoded protein may inhibit viral replication and translational initiation. This gene is located in a cluster on chromosome 10 with five other closely related genes. There is a pseudogene for this gene on chromosome 13. Alternatively spliced transcript variants encoding multiple isoforms have been observed. [provided by RefSeq, Aug 2012]

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: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP7: Synonymous conserved (PhyloP=-1.82 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.429 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001548.5. 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
	IFIT1	NM_001548.5	MANE Select	c.645C>T	p.Asp215Asp	synonymous	Exon 2 of 2	NP_001539.3	P09914-1
	IFIT1	NM_001270927.2		c.645C>T	p.Asp215Asp	synonymous	Exon 3 of 3	NP_001257856.1
	IFIT1	NM_001270928.2		c.552C>T	p.Asp184Asp	synonymous	Exon 3 of 3	NP_001257857.1	P09914-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IFIT1	ENST00000371804.4	TSL:1 MANE Select	c.645C>T	p.Asp215Asp	synonymous	Exon 2 of 2	ENSP00000360869.3	P09914-1
	IFIT1	ENST00000546318.2	TSL:3	c.552C>T	p.Asp184Asp	synonymous	Exon 3 of 3	ENSP00000441968.1	P09914-2
	LIPA	ENST00000868661.1		c.-2+9821G>A		intron	N/A	ENSP00000538720.1

Frequencies

GnomAD3 genomes AF: 0.175 AC: 26589 AN: 152068 Hom.: 2975 Cov.: 33

Gnomad AFR AF: 0.0550

Gnomad AMI AF: 0.150

Gnomad AMR AF: 0.239

Gnomad ASJ AF: 0.243

Gnomad EAS AF: 0.444

Gnomad SAS AF: 0.339

Gnomad FIN AF: 0.225

Gnomad MID AF: 0.152

Gnomad NFE AF: 0.190

Gnomad OTH AF: 0.181

GnomAD2 exomes AF: 0.241 AC: 60415 AN: 251204 AF XY: 0.244

Gnomad AFR exome AF: 0.0518

Gnomad AMR exome AF: 0.295

Gnomad ASJ exome AF: 0.232

Gnomad EAS exome AF: 0.460

Gnomad FIN exome AF: 0.212

Gnomad NFE exome AF: 0.191

Gnomad OTH exome AF: 0.233

GnomAD4 exome AF: 0.207 AC: 302406 AN: 1461710 Hom.: 34598 Cov.: 36 AF XY: 0.211 AC XY: 153764 AN XY: 727184

African (AFR) AF: 0.0490 AC: 1640 AN: 33480

American (AMR) AF: 0.289 AC: 12944 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.239 AC: 6247 AN: 26136

East Asian (EAS) AF: 0.432 AC: 17131 AN: 39698

South Asian (SAS) AF: 0.353 AC: 30423 AN: 86252

European-Finnish (FIN) AF: 0.213 AC: 11378 AN: 53366

Middle Eastern (MID) AF: 0.211 AC: 1219 AN: 5766

European-Non Finnish (NFE) AF: 0.188 AC: 208704 AN: 1111906

Other (OTH) AF: 0.211 AC: 12720 AN: 60394

GnomAD4 genome AF: 0.175 AC: 26590 AN: 152186 Hom.: 2974 Cov.: 33 AF XY: 0.182 AC XY: 13559 AN XY: 74394

African (AFR) AF: 0.0548 AC: 2277 AN: 41526

American (AMR) AF: 0.239 AC: 3650 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.243 AC: 842 AN: 3470

East Asian (EAS) AF: 0.444 AC: 2299 AN: 5178

South Asian (SAS) AF: 0.340 AC: 1642 AN: 4826

European-Finnish (FIN) AF: 0.225 AC: 2378 AN: 10576

Middle Eastern (MID) AF: 0.143 AC: 42 AN: 294

European-Non Finnish (NFE) AF: 0.190 AC: 12939 AN: 67996

Other (OTH) AF: 0.182 AC: 384 AN: 2114

Alfa AF: 0.175 Hom.: 4912

Bravo AF: 0.166

Asia WGS AF: 0.316 AC: 1099 AN: 3478

EpiCase AF: 0.190

EpiControl AF: 0.187

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.50
DANN	Benign	0.57
PhyloP100		-1.8
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: rs303210; hg19: chr10-91162677; COSMIC: COSV65661105;