rs139468837

Positions:

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_001023570.4(IQCB1):c.1549A>T(p.Asn517Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.00238 in 1,614,226 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0023 ( 3 hom., cov: 32)

Exomes 𝑓: 0.0024 ( 12 hom. )

Consequence

IQCB1
NM_001023570.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:8

Conservation

PhyloP100: 3.90

Variant links:

Genes affected

IQCB1 (HGNC:28949): (IQ motif containing B1) This gene encodes a nephrocystin protein that interacts with calmodulin and the retinitis pigmentosa GTPase regulator protein. The encoded protein has a central coiled-coil region and two calmodulin-binding IQ domains. It is localized to the primary cilia of renal epithelial cells and connecting cilia of photoreceptor cells. The protein is thought to play a role in ciliary function. Defects in this gene result in Senior-Loken syndrome type 5. Alternative splicing results in multiple transcript variants. A pseudogene of this gene is found on chromosome 6. [provided by RefSeq, Jan 2016]

IQCB1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.020065188).

BP6

Variant 3-121772575-T-A is Benign according to our data. Variant chr3-121772575-T-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 215481.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Benign=2, Uncertain_significance=1}. Variant chr3-121772575-T-A is described in Lovd as [Likely_benign].

BS2

High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IQCB1	NM_001023570.4 linkuse as main transcript	c.1549A>T	p.Asn517Tyr	missense_variant	14/15	ENST00000310864.11	NP_001018864.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IQCB1	ENST00000310864.11 linkuse as main transcript	c.1549A>T	p.Asn517Tyr	missense_variant	14/15	1	NM_001023570.4	ENSP00000311505	P1	Q15051-1
IQCB1	ENST00000349820.10 linkuse as main transcript	c.1150A>T	p.Asn384Tyr	missense_variant	11/12	1		ENSP00000323756		Q15051-2
IQCB1	ENST00000393650.7 linkuse as main transcript	c.*527A>T		3_prime_UTR_variant, NMD_transcript_variant	13/14	5		ENSP00000377261		Q15051-3

Frequencies

GnomAD3 genomes

AF:

0.00225

AC:

343

AN:

152222

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000386

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00118

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000413

Gnomad FIN

AF:

0.0136

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00234

Gnomad OTH

AF:

0.00191

GnomAD3 exomes

AF:

0.00237

AC:

596

AN:

251432

Hom.:

AF XY:

0.00210

AC XY:

285

AN XY:

135888

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.00142

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000555

Gnomad FIN exome

AF:

0.0116

Gnomad NFE exome

AF:

0.00235

Gnomad OTH exome

AF:

0.00179

GnomAD4 exome

AF:

0.00239

AC:

3499

AN:

1461886

Hom.:

Cov.:

AF XY:

0.00233

AC XY:

1697

AN XY:

727244

show subpopulations

Gnomad4 AFR exome

AF:

0.000179

Gnomad4 AMR exome

AF:

0.00141

Gnomad4 ASJ exome

AF:

0.0000765

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000614

Gnomad4 FIN exome

AF:

0.0118

Gnomad4 NFE exome

AF:

0.00235

Gnomad4 OTH exome

AF:

0.00217

GnomAD4 genome

AF:

0.00225

AC:

343

AN:

152340

Hom.:

Cov.:

AF XY:

0.00268

AC XY:

200

AN XY:

74500

show subpopulations

Gnomad4 AFR

AF:

0.000385

Gnomad4 AMR

AF:

0.00118

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000414

Gnomad4 FIN

AF:

0.0136

Gnomad4 NFE

AF:

0.00234

Gnomad4 OTH

AF:

0.00189

Alfa

AF:

0.00144

Hom.:

Bravo

AF:

0.00131

TwinsUK

AF:

0.00324

AC:

ALSPAC

AF:

0.00182

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00233

AC:

ExAC

AF:

0.00217

AC:

264

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:8

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:4

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 10, 2021	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 20, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jun 30, 2016	- -

Senior-Loken syndrome 5

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Nephronophthisis

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 19, 2024

- -

IQCB1-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 02, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Uncertain

-0.080

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.22

T;.

Eigen

Uncertain

0.43

Eigen_PC

Uncertain

0.37

FATHMM_MKL

Uncertain

0.84

LIST_S2

Benign

0.83

T;T

M_CAP

Uncertain

0.11

MetaRNN

Benign

0.020

T;T

MetaSVM

Uncertain

0.20

MutationAssessor

Uncertain

2.4

M;.

MutationTaster

Benign

0.66

D;D

PrimateAI

Uncertain

0.53

PROVEAN

Uncertain

-3.2

D;D

REVEL

Uncertain

0.43

Sift

Uncertain

0.0040

D;D

Sift4G

Uncertain

0.011

D;D

Polyphen

0.99

D;D

Vest4

0.59

MVP

0.91

MPC

0.36

ClinPred

0.063

GERP RS

5.0

Varity_R

0.12

gMVP

0.19

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over