rs1141528

Variant names:

• chr3-121788384-A-T
• rs1141528
• NM_001023570.4:c.1178T>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001023570.4(IQCB1):​c.1178T>A​(p.Ile393Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.117 in 1,613,104 control chromosomes in the GnomAD database, including 12,634 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.089 (813 hom., cov: 32)
  • Exomes 𝑓: 0.12 (11821 hom.)
• Consequence: IQCB1 NM_001023570.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10 O:1
• Conservation: PhyloP100: 1.34
• Publications: 37 publications found

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 Gene-Disease associations (from GenCC):

• Senior-Loken syndrome 5

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• Leber congenital amaurosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Senior-Loken syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.002072066).
• BP6: Variant 3-121788384-A-T is Benign according to our data. Variant chr3-121788384-A-T is described in ClinVar as Benign. ClinVar VariationId is 167196.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.13 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IQCB1	NM_001023570.4	c.1178T>A	p.Ile393Asn	missense_variant	Exon 12 of 15	ENST00000310864.11	NP_001018864.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IQCB1	ENST00000310864.11	c.1178T>A	p.Ile393Asn	missense_variant	Exon 12 of 15	1	NM_001023570.4	ENSP00000311505.6
IQCB1	ENST00000349820.10	c.779T>A	p.Ile260Asn	missense_variant	Exon 9 of 12	1		ENSP00000323756.7
IQCB1	ENST00000393650.7	n.*156T>A		non_coding_transcript_exon_variant	Exon 11 of 14	5		ENSP00000377261.3
IQCB1	ENST00000393650.7	n.*156T>A		3_prime_UTR_variant	Exon 11 of 14	5		ENSP00000377261.3

Frequencies

GnomAD3 genomes AF: 0.0894 AC: 13593 AN: 152082 Hom.: 813 Cov.: 32

Gnomad AFR AF: 0.0356

Gnomad AMI AF: 0.247

Gnomad AMR AF: 0.0633

Gnomad ASJ AF: 0.0980

Gnomad EAS AF: 0.00193

Gnomad SAS AF: 0.0257

Gnomad FIN AF: 0.119

Gnomad MID AF: 0.0823

Gnomad NFE AF: 0.132

Gnomad OTH AF: 0.0925

GnomAD2 exomes AF: 0.0914 AC: 22980 AN: 251436 AF XY: 0.0914

Gnomad AFR exome AF: 0.0350

Gnomad AMR exome AF: 0.0561

Gnomad ASJ exome AF: 0.0910

Gnomad EAS exome AF: 0.00272

Gnomad FIN exome AF: 0.117

Gnomad NFE exome AF: 0.137

Gnomad OTH exome AF: 0.0934

GnomAD4 exome AF: 0.120 AC: 174882 AN: 1460904 Hom.: 11821 Cov.: 31 AF XY: 0.117 AC XY: 84776 AN XY: 726770

African (AFR) AF: 0.0295 AC: 987 AN: 33466

American (AMR) AF: 0.0584 AC: 2610 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0854 AC: 2231 AN: 26126

East Asian (EAS) AF: 0.00184 AC: 73 AN: 39674

South Asian (SAS) AF: 0.0295 AC: 2547 AN: 86242

European-Finnish (FIN) AF: 0.117 AC: 6266 AN: 53370

Middle Eastern (MID) AF: 0.0553 AC: 319 AN: 5764

European-Non Finnish (NFE) AF: 0.138 AC: 153698 AN: 1111180

Other (OTH) AF: 0.102 AC: 6151 AN: 60358

GnomAD4 genome AF: 0.0893 AC: 13591 AN: 152200 Hom.: 813 Cov.: 32 AF XY: 0.0856 AC XY: 6367 AN XY: 74398

African (AFR) AF: 0.0354 AC: 1472 AN: 41556

American (AMR) AF: 0.0631 AC: 966 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0980 AC: 340 AN: 3468

East Asian (EAS) AF: 0.00193 AC: 10 AN: 5180

South Asian (SAS) AF: 0.0261 AC: 126 AN: 4828

European-Finnish (FIN) AF: 0.119 AC: 1254 AN: 10564

Middle Eastern (MID) AF: 0.0850 AC: 25 AN: 294

European-Non Finnish (NFE) AF: 0.132 AC: 8982 AN: 67994

Other (OTH) AF: 0.0911 AC: 192 AN: 2108

Alfa AF: 0.118 Hom.: 349

Bravo AF: 0.0868

TwinsUK AF: 0.149 AC: 551

ALSPAC AF: 0.134 AC: 515

ESP6500AA AF: 0.0370 AC: 163

ESP6500EA AF: 0.130 AC: 1118

ExAC AF: 0.0931 AC: 11300

Asia WGS AF: 0.0200 AC: 69 AN: 3478

EpiCase AF: 0.128

EpiControl AF: 0.131

ClinVar

Significance: Benign

Submissions summary: Benign:10 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Apr 28, 2014

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Senior-Loken syndrome 5 Benign:2

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Jan 18, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: research

- -

not provided Benign:2

Nov 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 22183348) -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nephronophthisis Benign:1 Other:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.091	T;.
Eigen	Benign	-0.042
Eigen_PC	Benign	0.020
FATHMM_MKL	Benign	0.72	D
LIST_S2	Uncertain	0.91	D;D
MetaRNN	Benign	0.0021	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.0	M;.
PhyloP100		1.3
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-1.3	N;N
REVEL	Benign	0.021
Sift	Benign	0.064	T;D
Sift4G	Uncertain	0.020	D;D
Polyphen		0.81	P;P
Vest4		0.26
MPC		0.46
ClinPred		0.022	T
GERP RS		2.2
Varity_R		0.29
gMVP		0.34
Mutation Taster		=94/6	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1141528; hg19: chr3-121507231; COSMIC: COSV60438765;