rs1727

Variant names:

• chr10-89307012-C-A
• rs1727
• NM_001547.5:c.1056C>A

Your query was ambiguous. Multiple possible variants found:

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

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000371826.4(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. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.82 (52344 hom., cov: 30)
  • Exomes 𝑓: 0.76 (423086 hom.)
• Consequence: IFIT2 ENST00000371826.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.871
• Publications: 55 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 -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000371826.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IFIT2	NM_001547.5	MANE Select	c.1056C>A	p.Asp352Glu	missense	Exon 2 of 2	NP_001538.4
	LIPA	NM_001440836.1		c.131+7531G>T		intron	N/A	NP_001427765.1
	LIPA	NM_001440838.1		c.14+35549G>T		intron	N/A	NP_001427767.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IFIT2	ENST00000371826.4	TSL:1 MANE Select	c.1056C>A	p.Asp352Glu	missense	Exon 2 of 2	ENSP00000360891.3
	LIPA	ENST00000487618.5	TSL:1	n.181+7531G>T		intron	N/A
	IFIT2	ENST00000638108.1	TSL:5	c.1056C>A	p.Asp352Glu	missense	Exon 5 of 5	ENSP00000490935.1

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

GnomAD2 exomes AF: 0.795 AC: 198067 AN: 249018 AF XY: 0.796

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 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

African (AFR) AF: 0.961 AC: 32187 AN: 33476

American (AMR) AF: 0.720 AC: 32192 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.797 AC: 20836 AN: 26132

East Asian (EAS) AF: 0.982 AC: 38992 AN: 39688

South Asian (SAS) AF: 0.842 AC: 72655 AN: 86252

European-Finnish (FIN) AF: 0.804 AC: 42948 AN: 53394

Middle Eastern (MID) AF: 0.805 AC: 4645 AN: 5768

European-Non Finnish (NFE) AF: 0.735 AC: 816740 AN: 1111754

Other (OTH) AF: 0.778 AC: 46954 AN: 60386

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

African (AFR) AF: 0.951 AC: 39475 AN: 41502

American (AMR) AF: 0.764 AC: 11664 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.799 AC: 2774 AN: 3470

East Asian (EAS) AF: 0.987 AC: 5099 AN: 5168

South Asian (SAS) AF: 0.851 AC: 4105 AN: 4822

European-Finnish (FIN) AF: 0.818 AC: 8661 AN: 10582

Middle Eastern (MID) AF: 0.776 AC: 228 AN: 294

European-Non Finnish (NFE) AF: 0.748 AC: 50883 AN: 67988

Other (OTH) AF: 0.815 AC: 1723 AN: 2114

Alfa AF: 0.772 Hom.: 200767

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 v4.9

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
Eigen	Benign	-1.2
Eigen_PC	Benign	-0.92
FATHMM_MKL	Benign	0.067	N
LIST_S2	Benign	0.048	T
MetaRNN	Benign	9.0e-7	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	-2.2	N
PhyloP100		0.87
PrimateAI	Benign	0.27	T
PROVEAN	Benign	1.9	N
REVEL	Benign	0.033
Sift	Benign	0.98	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.016
MutPred		0.32		Gain of disorder (P = 0.1214)
MPC		0.16
ClinPred		0.0035	T
GERP RS		2.2
Varity_R		0.029
gMVP		0.072
Mutation Taster		=99/1	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: rs1727; hg19: chr10-91066769; COSMIC: COSV107295020;