rs1141528

Variant names:

• chr3-121788384-A-T
• rs1141528
• NM_001023570.4:c.1178T>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001023570.4(IQCB1):​c.1178T>A​(p.Ile393Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.117 in 1,613,104 control chromosomes in the GnomAD database, including 12,634 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.089 (813 hom., cov: 32)
  • Exomes 𝑓: 0.12 (11821 hom.)
• Consequence: IQCB1 NM_001023570.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10 O:1
• Conservation: PhyloP100: 1.34
• Publications: 37 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.002072066).
• BP6: Variant 3-121788384-A-T is Benign according to our data. Variant chr3-121788384-A-T is described in ClinVar as Benign. ClinVar VariationId is 167196.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.13 is higher than 0.05.

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.1178T>A	p.Ile393Asn	missense	Exon 12 of 15	NP_001018864.2	Q15051-1
	IQCB1	NM_001319107.2		c.1178T>A	p.Ile393Asn	missense	Exon 12 of 15	NP_001306036.1	Q15051-1
	IQCB1	NM_001023571.4		c.779T>A	p.Ile260Asn	missense	Exon 9 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.1178T>A	p.Ile393Asn	missense	Exon 12 of 15	ENSP00000311505.6	Q15051-1
	IQCB1	ENST00000349820.10	TSL:1	c.779T>A	p.Ile260Asn	missense	Exon 9 of 12	ENSP00000323756.7	Q15051-2
	IQCB1	ENST00000923631.1		c.1250T>A	p.Ile417Asn	missense	Exon 13 of 16	ENSP00000593690.1

Frequencies

GnomAD3 genomes AF: 0.0894 AC: 13593 AN: 152082 Hom.: 813 Cov.: 32

Gnomad AFR AF: 0.0356

Gnomad AMI AF: 0.247

Gnomad AMR AF: 0.0633

Gnomad ASJ AF: 0.0980

Gnomad EAS AF: 0.00193

Gnomad SAS AF: 0.0257

Gnomad FIN AF: 0.119

Gnomad MID AF: 0.0823

Gnomad NFE AF: 0.132

Gnomad OTH AF: 0.0925

GnomAD2 exomes AF: 0.0914 AC: 22980 AN: 251436 AF XY: 0.0914

Gnomad AFR exome AF: 0.0350

Gnomad AMR exome AF: 0.0561

Gnomad ASJ exome AF: 0.0910

Gnomad EAS exome AF: 0.00272

Gnomad FIN exome AF: 0.117

Gnomad NFE exome AF: 0.137

Gnomad OTH exome AF: 0.0934

GnomAD4 exome AF: 0.120 AC: 174882 AN: 1460904 Hom.: 11821 Cov.: 31 AF XY: 0.117 AC XY: 84776 AN XY: 726770

African (AFR) AF: 0.0295 AC: 987 AN: 33466

American (AMR) AF: 0.0584 AC: 2610 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0854 AC: 2231 AN: 26126

East Asian (EAS) AF: 0.00184 AC: 73 AN: 39674

South Asian (SAS) AF: 0.0295 AC: 2547 AN: 86242

European-Finnish (FIN) AF: 0.117 AC: 6266 AN: 53370

Middle Eastern (MID) AF: 0.0553 AC: 319 AN: 5764

European-Non Finnish (NFE) AF: 0.138 AC: 153698 AN: 1111180

Other (OTH) AF: 0.102 AC: 6151 AN: 60358

GnomAD4 genome AF: 0.0893 AC: 13591 AN: 152200 Hom.: 813 Cov.: 32 AF XY: 0.0856 AC XY: 6367 AN XY: 74398

African (AFR) AF: 0.0354 AC: 1472 AN: 41556

American (AMR) AF: 0.0631 AC: 966 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0980 AC: 340 AN: 3468

East Asian (EAS) AF: 0.00193 AC: 10 AN: 5180

South Asian (SAS) AF: 0.0261 AC: 126 AN: 4828

European-Finnish (FIN) AF: 0.119 AC: 1254 AN: 10564

Middle Eastern (MID) AF: 0.0850 AC: 25 AN: 294

European-Non Finnish (NFE) AF: 0.132 AC: 8982 AN: 67994

Other (OTH) AF: 0.0911 AC: 192 AN: 2108

Alfa AF: 0.118 Hom.: 349

Bravo AF: 0.0868

TwinsUK AF: 0.149 AC: 551

ALSPAC AF: 0.134 AC: 515

ESP6500AA AF: 0.0370 AC: 163

ESP6500EA AF: 0.130 AC: 1118

ExAC AF: 0.0931 AC: 11300

Asia WGS AF: 0.0200 AC: 69 AN: 3478

EpiCase AF: 0.128

EpiControl AF: 0.131

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	2	not provided (2)
-	-	2	Senior-Loken syndrome 5 (2)
-	-	1	Nephronophthisis (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.091	T
Eigen	Benign	-0.042
Eigen_PC	Benign	0.020
FATHMM_MKL	Benign	0.72	D
LIST_S2	Uncertain	0.91	D
MetaRNN	Benign	0.0021	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		1.3
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.021
Sift	Benign	0.064	T
Sift4G	Uncertain	0.020	D
Polyphen		0.81	P
Vest4		0.26
MPC		0.46
ClinPred		0.022	T
GERP RS		2.2
Varity_R		0.29
gMVP		0.34
Mutation Taster		=94/6	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1141528; hg19: chr3-121507231; COSMIC: COSV60438765;