rs387907009

chr3-121790166-C-Achr3-121790166-C-Gchr3-121790166-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.Glu346Ter) 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]

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	UniProt
IQCB1	NM_001023570.4	c.1036G>T	p.Glu346Ter	stop_gained	11/15	ENST00000310864.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IQCB1	ENST00000310864.11	c.1036G>T	p.Glu346Ter	stop_gained	11/15	1	NM_001023570.4	P1
IQCB1	ENST00000349820.10	c.637G>T	p.Glu213Ter	stop_gained	8/12	1
IQCB1	ENST00000393650.7	c.*14G>T		3_prime_UTR_variant, NMD_transcript_variant	10/14	5

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, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 30, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Nov 13, 2021	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 2011	- -
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. -

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

Invitae

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
MutationTaster	Benign	1.0	A;A
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;