rs387907009

Variant names:

• chr3-121790166-C-A
• rs387907009
• NM_001023570.4:c.1036G>T

Your query was ambiguous. Multiple possible variants found:

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

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1 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
• Publications: 10 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):

• ciliopathy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• Senior-Loken syndrome 5

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

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

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 3-121790166-C-A is Pathogenic according to our data. Variant chr3-121790166-C-A is described in ClinVar as Pathogenic. ClinVar VariationId is 30779.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001023570.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IQCB1	NM_001023570.4	MANE Select	c.1036G>T	p.Glu346*	stop_gained	Exon 11 of 15	NP_001018864.2	Q15051-1
	IQCB1	NM_001319107.2		c.1036G>T	p.Glu346*	stop_gained	Exon 11 of 15	NP_001306036.1	Q15051-1
	IQCB1	NM_001023571.4		c.637G>T	p.Glu213*	stop_gained	Exon 8 of 12	NP_001018865.2	Q15051-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IQCB1	ENST00000310864.11	TSL:1 MANE Select	c.1036G>T	p.Glu346*	stop_gained	Exon 11 of 15	ENSP00000311505.6	Q15051-1
	IQCB1	ENST00000349820.10	TSL:1	c.637G>T	p.Glu213*	stop_gained	Exon 8 of 12	ENSP00000323756.7	Q15051-2
	IQCB1	ENST00000923631.1		c.1108G>T	p.Glu370*	stop_gained	Exon 12 of 16	ENSP00000593690.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000119 AC: 3 AN: 251416 AF XY: 0.00

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 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

African (AFR) AF: 0.00 AC: 0 AN: 33468

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39664

South Asian (SAS) AF: 0.00 AC: 0 AN: 86234

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.0000234 AC: 26 AN: 1111600

Other (OTH) AF: 0.0000497 AC: 3 AN: 60368

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000330 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
4	-	-	Senior-Loken syndrome 5 (4)
1	-	-	Leber congenital amaurosis (1)
1	-	-	Nephronophthisis (1)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		1.8
Vest4		0.22
GERP RS		2.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=1/199	disease causing (ClinVar)

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

Other links and lift over

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