rs552311575

Variant names:

• chr3-121770127-C-T
• rs552311575
• NM_001023570.4:c.*218G>A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The NM_001023570.4(IQCB1):​c.*218G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00112 in 531,250 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0011 (3 hom., cov: 33)
  • Exomes 𝑓: 0.0012 (0 hom.)
• Consequence: IQCB1 NM_001023570.4 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.331

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 Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00105 (160/152252) while in subpopulation AMR AF= 0.00373 (57/15300). AF 95% confidence interval is 0.00295. There are 3 homozygotes in gnomad4. There are 98 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IQCB1	NM_001023570.4	c.*218G>A		3_prime_UTR_variant	Exon 15 of 15	ENST00000310864.11	NP_001018864.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IQCB1	ENST00000310864	c.*218G>A		3_prime_UTR_variant	Exon 15 of 15	1	NM_001023570.4	ENSP00000311505.6
IQCB1	ENST00000349820	c.*218G>A		3_prime_UTR_variant	Exon 12 of 12	1		ENSP00000323756.7
IQCB1	ENST00000393650.7	n.*993G>A		non_coding_transcript_exon_variant	Exon 14 of 14	5		ENSP00000377261.3
IQCB1	ENST00000393650.7	n.*993G>A		3_prime_UTR_variant	Exon 14 of 14	5		ENSP00000377261.3

Frequencies

GnomAD3 genomes AF: 0.00105 AC: 160 AN: 152134 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.000338

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00373

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000378

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00125

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00115 AC: 436 AN: 378998 Hom.: 0 Cov.: 0 AF XY: 0.000975 AC XY: 194 AN XY: 198908

Gnomad4 AFR exome AF: 0.000177

Gnomad4 AMR exome AF: 0.00249

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000515

Gnomad4 FIN exome AF: 0.000728

Gnomad4 NFE exome AF: 0.00154

Gnomad4 OTH exome AF: 0.00108

GnomAD4 genome AF: 0.00105 AC: 160 AN: 152252 Hom.: 3 Cov.: 33 AF XY: 0.00132 AC XY: 98 AN XY: 74446

Gnomad4 AFR AF: 0.000337

Gnomad4 AMR AF: 0.00373

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000378

Gnomad4 NFE AF: 0.00125

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000900 Hom.: 0

Bravo AF: 0.00113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Senior-Loken syndrome 5 Uncertain:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	3.8
DANN	Benign	0.64
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		0.97

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: rs552311575; hg19: chr3-121488974;