3-121790112-G-A

Position:

chr3-121790112-G-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_001023570.4(IQCB1):c.1090C>T(p.Arg364*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000328 in 1,613,438 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: 𝑓 0.000059 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000030 ( 0 hom. )

Consequence

IQCB1
NM_001023570.4 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 3.33

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:

IQCB1 (HGNC:):

IQCB1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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 3-121790112-G-A is Pathogenic according to our data. Variant chr3-121790112-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 167197.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-121790112-G-A is described in Lovd as [Pathogenic]. Variant chr3-121790112-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IQCB1	NM_001023570.4 linkuse as main transcript	c.1090C>T	p.Arg364*	stop_gained	11/15	ENST00000310864.11	NP_001018864.2	Q15051-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
IQCB1	ENST00000310864.11 linkuse as main transcript	c.1090C>T	p.Arg364*	stop_gained	11/15	1	NM_001023570.4	ENSP00000311505.6	Q15051-1
IQCB1	ENST00000349820.10 linkuse as main transcript	c.691C>T	p.Arg231*	stop_gained	8/12	1		ENSP00000323756.7	Q15051-2
IQCB1	ENST00000393650.7 linkuse as main transcript	n.*68C>T		non_coding_transcript_exon_variant	10/14	5		ENSP00000377261.3	Q15051-3
IQCB1	ENST00000393650.7 linkuse as main transcript	n.*68C>T		3_prime_UTR_variant	10/14	5		ENSP00000377261.3	Q15051-3

Frequencies

GnomAD3 genomes

AF:

0.0000592

AC:

AN:

152072

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00154

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000557

AC:

AN:

251366

Hom.:

AF XY:

0.0000662

AC XY:

AN XY:

135856

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000707

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000301

AC:

AN:

1461366

Hom.:

Cov.:

AF XY:

0.0000248

AC XY:

AN XY:

727032

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000277

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000279

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000592

AC:

AN:

152072

Hom.:

Cov.:

AF XY:

0.0000673

AC XY:

AN XY:

74306

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00154

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.00000799

Hom.:

Bravo

AF:

0.0000529

ExAC

AF:

0.0000494

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Senior-Loken syndrome 5

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	3billion	May 22, 2022	Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.008%). The variant has been reported at least twice as pathogenic without evidence for the classification (ClinVar ID: VCV000167197 / PMID: 19430481 / 3billion dataset). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 08, 2024	- -

Nephronophthisis

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 17, 2023

This sequence change creates a premature translational stop signal (p.Arg364*) 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). This variant is present in population databases (rs727503968, gnomAD 0.1%). This premature translational stop signal has been observed in individuals with Senior-L√∏ken syndrome and Leber congenital amaurosis (PMID: 19430481, 23661368, 24674142, 26274329). ClinVar contains an entry for this variant (Variation ID: 167197). For these reasons, this variant has been classified as Pathogenic. -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Feb 05, 2014

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.29

BayesDel_noAF

Pathogenic

0.59

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Uncertain

0.61

Eigen_PC

Uncertain

0.42

FATHMM_MKL

Uncertain

0.89

Vest4

0.24

GERP RS

4.0

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