10-89383876-T-C

Position:

• chr10-89383876-T-C

Variant summary

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

The NM_001010987.2(IFIT1B):​c.563T>C​(p.Leu188Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00236 in 1,614,206 control chromosomes in the GnomAD database, including 81 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.013 (41 hom., cov: 32)
  • Exomes 𝑓: 0.0013 (40 hom.)
• Consequence: IFIT1B NM_001010987.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.981

Genes affected

IFIT1B (HGNC:23442): (interferon induced protein with tetratricopeptide repeats 1B) Predicted to enable RNA binding activity. Predicted to be involved in defense response to virus. Predicted to act upstream of or within cellular response to interferon-alpha; cellular response to interferon-beta; and response to bacterium. Predicted to be located in cytoplasm. Predicted to be active in cytosol. [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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.007154584).
• BP6: Variant 10-89383876-T-C is Benign according to our data. Variant chr10-89383876-T-C is described in ClinVar as [Benign]. Clinvar id is 720003.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0129 (1967/152320) while in subpopulation AFR AF= 0.0453 (1883/41570). AF 95% confidence interval is 0.0436. There are 41 homozygotes in gnomad4. There are 901 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 41 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IFIT1B	NM_001010987.2	c.563T>C	p.Leu188Pro	missense_variant	2/2	ENST00000371809.3	NP_001010987.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IFIT1B	ENST00000371809.3	c.563T>C	p.Leu188Pro	missense_variant	2/2	1	NM_001010987.2	ENSP00000360874.3
LIPA	ENST00000371837.5	c.61+28915A>G		intron_variant		2		ENSP00000360903.1

Frequencies

GnomAD3 genomes AF: 0.0129 AC: 1964 AN: 152202 Hom.: 40 Cov.: 32

Gnomad AFR AF: 0.0454

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00399

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00765

GnomAD3 exomes AF: 0.00341 AC: 856 AN: 251132 Hom.: 22 AF XY: 0.00239 AC XY: 325 AN XY: 135720

Gnomad AFR exome AF: 0.0481

Gnomad AMR exome AF: 0.00185

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000617

Gnomad OTH exome AF: 0.000653

GnomAD4 exome AF: 0.00126 AC: 1841 AN: 1461886 Hom.: 40 Cov.: 34 AF XY: 0.00105 AC XY: 760 AN XY: 727242

Gnomad4 AFR exome AF: 0.0459

Gnomad4 AMR exome AF: 0.00199

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000342

Gnomad4 OTH exome AF: 0.00275

GnomAD4 genome AF: 0.0129 AC: 1967 AN: 152320 Hom.: 41 Cov.: 32 AF XY: 0.0121 AC XY: 901 AN XY: 74488

Gnomad4 AFR AF: 0.0453

Gnomad4 AMR AF: 0.00399

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.00757

Alfa AF: 0.00251 Hom.: 9

Bravo AF: 0.0148

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0472 AC: 208

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00425 AC: 516

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.000119

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	Mar 30, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.42
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	18
DANN	Uncertain	1.0
DEOGEN2	Benign	0.30	T
Eigen	Benign	0.067
Eigen_PC	Benign	-0.19
FATHMM_MKL	Benign	0.74	D
LIST_S2	Benign	0.81	T
MetaRNN	Benign	0.0072	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Pathogenic	3.4	M
PrimateAI	Benign	0.40	T
PROVEAN	Pathogenic	-5.2	D
REVEL	Benign	0.090
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.42
MVP		0.79
MPC		0.048
ClinPred		0.096	T
GERP RS		0.35
Varity_R		0.75
gMVP		0.51

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: rs7072728; hg19: chr10-91143633;