rs387907009

Positions:

• chr3-121790166-C-A
• chr3-121790166-C-G
• chr3-121790166-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_001023570.4(IQCB1):​c.1036G>T​(p.Glu346*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000198 in 1,461,368 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000020 (0 hom.)
• Consequence: IQCB1 NM_001023570.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 1.77

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 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 3-121790166-C-A is Pathogenic according to our data. Variant chr3-121790166-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 30779.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-121790166-C-A is described in Lovd as [Likely_pathogenic]. Variant chr3-121790166-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IQCB1	NM_001023570.4	c.1036G>T	p.Glu346*	stop_gained	11/15	ENST00000310864.11	NP_001018864.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IQCB1	ENST00000310864.11	c.1036G>T	p.Glu346*	stop_gained	11/15	1	NM_001023570.4	ENSP00000311505.6
IQCB1	ENST00000349820.10	c.637G>T	p.Glu213*	stop_gained	8/12	1		ENSP00000323756.7
IQCB1	ENST00000393650.7	n.*14G>T		non_coding_transcript_exon_variant	10/14	5		ENSP00000377261.3
IQCB1	ENST00000393650.7	n.*14G>T		3_prime_UTR_variant	10/14	5		ENSP00000377261.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000119 AC: 3 AN: 251416 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135878

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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: 0.0000176

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000198 AC: 29 AN: 1461368 Hom.: 0 Cov.: 30 AF XY: 0.0000151 AC XY: 11 AN XY: 727016

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000234

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000557 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Senior-Loken syndrome 5 Pathogenic:4

Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 2011	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 04, 2024	- -
Pathogenic, criteria provided, single submitter	research	Ocular Genomics Institute, Massachusetts Eye and Ear	Apr 08, 2021	The IQCB1 c.1036G>T variant was identified in an individual with retinitis pigmentosa with a presumed recessive inheritance pattern. Through a review of available evidence we were able to apply the following criteria: PVS1, PM2, PM3, PP1-M, PS3. Based on this evidence we have classified this variant as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Feb 21, 2024	- -

Leber congenital amaurosis Pathogenic:1

Pathogenic, no assertion criteria provided

research

NIHR Bioresource Rare Diseases, University of Cambridge

Jan 01, 2015

- -

Nephronophthisis Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 30, 2022

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 30779). This premature translational stop signal has been observed in individuals with Leber congenital amaurosis (PMID: 21220633, 27624628). This variant is present in population databases (rs387907009, gnomAD 0.0009%). This sequence change creates a premature translational stop signal (p.Glu346*) in the IQCB1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in IQCB1 are known to be pathogenic (PMID: 15723066, 21901789, 23559409, 28041643). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.57
CADD	Pathogenic	36
DANN	Uncertain	1.0
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Uncertain	0.90	D
Vest4		0.22
GERP RS		2.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs387907009; hg19: chr3-121509013; COSMIC: COSV60438872;