chr10-89306689-G-C

Position:

• chr10-89306689-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001547.5(IFIT2):​c.733G>C​(p.Gly245Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00666 in 1,614,108 control chromosomes in the GnomAD database, including 54 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0055 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0068 (51 hom.)
• Consequence: IFIT2 NM_001547.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.942

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:):

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0033566654).
• BP6: Variant 10-89306689-G-C is Benign according to our data. Variant chr10-89306689-G-C is described in ClinVar as [Benign]. Clinvar id is 787589.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.00678 (9916/1461790) while in subpopulation MID AF= 0.031 (179/5768). AF 95% confidence interval is 0.0273. There are 51 homozygotes in gnomad4_exome. There are 4991 alleles in male gnomad4_exome subpopulation. Median coverage is 35. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IFIT2	NM_001547.5	c.733G>C	p.Gly245Arg	missense_variant	2/2	ENST00000371826.4	NP_001538.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IFIT2	ENST00000371826.4	c.733G>C	p.Gly245Arg	missense_variant	2/2	1	NM_001547.5	ENSP00000360891.3

Frequencies

GnomAD3 genomes AF: 0.00549 AC: 835 AN: 152200 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00191

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.00386

Gnomad ASJ AF: 0.00231

Gnomad EAS AF: 0.0123

Gnomad SAS AF: 0.00352

Gnomad FIN AF: 0.00565

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.00760

Gnomad OTH AF: 0.0100

GnomAD3 exomes AF: 0.00674 AC: 1681 AN: 249458 Hom.: 9 AF XY: 0.00715 AC XY: 967 AN XY: 135328

Gnomad AFR exome AF: 0.00129

Gnomad AMR exome AF: 0.00380

Gnomad ASJ exome AF: 0.00407

Gnomad EAS exome AF: 0.0117

Gnomad SAS exome AF: 0.00510

Gnomad FIN exome AF: 0.00575

Gnomad NFE exome AF: 0.00822

Gnomad OTH exome AF: 0.0111

GnomAD4 exome AF: 0.00678 AC: 9916 AN: 1461790 Hom.: 51 Cov.: 35 AF XY: 0.00686 AC XY: 4991 AN XY: 727208

Gnomad4 AFR exome AF: 0.00248

Gnomad4 AMR exome AF: 0.00394

Gnomad4 ASJ exome AF: 0.00467

Gnomad4 EAS exome AF: 0.0113

Gnomad4 SAS exome AF: 0.00417

Gnomad4 FIN exome AF: 0.00621

Gnomad4 NFE exome AF: 0.00701

Gnomad4 OTH exome AF: 0.00700

GnomAD4 genome AF: 0.00546 AC: 832 AN: 152318 Hom.: 3 Cov.: 32 AF XY: 0.00517 AC XY: 385 AN XY: 74486

Gnomad4 AFR AF: 0.00190

Gnomad4 AMR AF: 0.00386

Gnomad4 ASJ AF: 0.00231

Gnomad4 EAS AF: 0.0123

Gnomad4 SAS AF: 0.00332

Gnomad4 FIN AF: 0.00565

Gnomad4 NFE AF: 0.00760

Gnomad4 OTH AF: 0.00992

Alfa AF: 0.00732 Hom.: 6

Bravo AF: 0.00571

TwinsUK AF: 0.00755 AC: 28

ALSPAC AF: 0.00778 AC: 30

ESP6500AA AF: 0.00151 AC: 6

ESP6500EA AF: 0.00740 AC: 62

ExAC AF: 0.00700 AC: 847

Asia WGS AF: 0.00953 AC: 33 AN: 3478

EpiCase AF: 0.00922

EpiControl AF: 0.00848

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	May 21, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	0.020
DANN	Benign	0.65
DEOGEN2	Benign	0.037	T;T;.
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.037	N
LIST_S2	Benign	0.033	.;T;T
MetaRNN	Benign	0.0034	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.26	N;N;.
PrimateAI	Benign	0.18	T
PROVEAN	Benign	-1.3	.;N;.
REVEL	Benign	0.016
Sift	Benign	0.26	.;T;.
Sift4G	Benign	0.21	.;T;T
Polyphen		0.0	B;B;.
Vest4		0.12, 0.12
MVP		0.17
MPC		0.21
ClinPred		0.00026	T
GERP RS		-6.0
Varity_R		0.057
gMVP		0.16

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: rs41284134; hg19: chr10-91066446; COSMIC: COSV51080659;