rs11920543

Positions:

• chr3-121781850-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001023570.4(IQCB1):​c.1303C>T​(p.Arg435Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0119 in 1,613,480 control chromosomes in the GnomAD database, including 264 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R435H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.011 (17 hom., cov: 31)
  • Exomes 𝑓: 0.012 (247 hom.)
• Consequence: IQCB1 NM_001023570.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 4.39

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0036824048).
• BP6: Variant 3-121781850-G-A is Benign according to our data. Variant chr3-121781850-G-A is described in ClinVar as [Benign]. Clinvar id is 219524.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-121781850-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.011 (1679/152074) while in subpopulation NFE AF= 0.0129 (878/68000). AF 95% confidence interval is 0.0122. There are 17 homozygotes in gnomad4. There are 952 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 17 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IQCB1	NM_001023570.4	c.1303C>T	p.Arg435Cys	missense_variant	13/15	ENST00000310864.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IQCB1	ENST00000310864.11	c.1303C>T	p.Arg435Cys	missense_variant	13/15	1	NM_001023570.4	P1
IQCB1	ENST00000349820.10	c.904C>T	p.Arg302Cys	missense_variant	10/12	1
IQCB1	ENST00000393650.7	c.*281C>T		3_prime_UTR_variant, NMD_transcript_variant	12/14	5

Frequencies

GnomAD3 genomes AF: 0.0111 AC: 1680 AN: 151954 Hom.: 17 Cov.: 31

Gnomad AFR AF: 0.00138

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00157

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.000416

Gnomad FIN AF: 0.0664

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0129

Gnomad OTH AF: 0.00860

GnomAD3 exomes AF: 0.0139 AC: 3501 AN: 251390 Hom.: 75 AF XY: 0.0134 AC XY: 1814 AN XY: 135862

Gnomad AFR exome AF: 0.00203

Gnomad AMR exome AF: 0.000752

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000196

Gnomad FIN exome AF: 0.0625

Gnomad NFE exome AF: 0.0176

Gnomad OTH exome AF: 0.0129

GnomAD4 exome AF: 0.0120 AC: 17566 AN: 1461406 Hom.: 247 Cov.: 32 AF XY: 0.0115 AC XY: 8360 AN XY: 727042

Gnomad4 AFR exome AF: 0.00131

Gnomad4 AMR exome AF: 0.000895

Gnomad4 ASJ exome AF: 0.000345

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000220

Gnomad4 FIN exome AF: 0.0615

Gnomad4 NFE exome AF: 0.0122

Gnomad4 OTH exome AF: 0.00963

GnomAD4 genome AF: 0.0110 AC: 1679 AN: 152074 Hom.: 17 Cov.: 31 AF XY: 0.0128 AC XY: 952 AN XY: 74310

Gnomad4 AFR AF: 0.00137

Gnomad4 AMR AF: 0.00157

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.0664

Gnomad4 NFE AF: 0.0129

Gnomad4 OTH AF: 0.00851

Alfa AF: 0.0106 Hom.: 5

Bravo AF: 0.00609

TwinsUK AF: 0.0121 AC: 45

ALSPAC AF: 0.0104 AC: 40

ESP6500AA AF: 0.00272 AC: 12

ESP6500EA AF: 0.0149 AC: 128

ExAC AF: 0.0156 AC: 1896

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Senior-Loken syndrome 5 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Nephronophthisis Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Aug 31, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.19
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.34	T;.
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Uncertain	0.89	D;D
MetaRNN	Benign	0.0037	T;T
MetaSVM	Uncertain	-0.012	T
MutationAssessor	Uncertain	2.4	M;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.25	T
PROVEAN	Uncertain	-4.2	D;D
REVEL	Uncertain	0.32
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.0020	D;D
Polyphen		1.0	D;D
Vest4		0.15
MPC		0.40
ClinPred		0.037	T
GERP RS		4.6
Varity_R		0.26
gMVP		0.42

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: rs11920543; hg19: chr3-121500697; COSMIC: COSV60436827;