NM_001023570.4:c.1303C>T

Variant names:

• chr3-121781850-G-A
• rs11920543
• NM_001023570.4:c.1303C>T

Variant summary

Our verdict is Benign. The variant received -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:6
• Conservation: PhyloP100: 4.39
• Publications: 12 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):

• Senior-Loken syndrome 5

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• 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=0.0036824048).
• BP6: Variant 3-121781850-G-A is Benign according to our data. Variant chr3-121781850-G-A is described in ClinVar as Benign. ClinVar VariationId is 219524.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 17 AD,AR gene

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.1303C>T	p.Arg435Cys	missense	Exon 13 of 15	NP_001018864.2
	IQCB1	NM_001319107.2		c.1303C>T	p.Arg435Cys	missense	Exon 13 of 15	NP_001306036.1
	IQCB1	NM_001023571.4		c.904C>T	p.Arg302Cys	missense	Exon 10 of 12	NP_001018865.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IQCB1	ENST00000310864.11	TSL:1 MANE Select	c.1303C>T	p.Arg435Cys	missense	Exon 13 of 15	ENSP00000311505.6
	IQCB1	ENST00000349820.10	TSL:1	c.904C>T	p.Arg302Cys	missense	Exon 10 of 12	ENSP00000323756.7
	IQCB1	ENST00000923631.1		c.1375C>T	p.Arg459Cys	missense	Exon 14 of 16	ENSP00000593690.1

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

GnomAD2 exomes AF: 0.0139 AC: 3501 AN: 251390 AF XY: 0.0134

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 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

African (AFR) AF: 0.00131 AC: 44 AN: 33472

American (AMR) AF: 0.000895 AC: 40 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.000345 AC: 9 AN: 26122

East Asian (EAS) AF: 0.00 AC: 0 AN: 39670

South Asian (SAS) AF: 0.000220 AC: 19 AN: 86238

European-Finnish (FIN) AF: 0.0615 AC: 3281 AN: 53380

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

European-Non Finnish (NFE) AF: 0.0122 AC: 13592 AN: 1111684

Other (OTH) AF: 0.00963 AC: 581 AN: 60362

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

African (AFR) AF: 0.00137 AC: 57 AN: 41488

American (AMR) AF: 0.00157 AC: 24 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5184

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4806

European-Finnish (FIN) AF: 0.0664 AC: 700 AN: 10548

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0129 AC: 878 AN: 68000

Other (OTH) AF: 0.00851 AC: 18 AN: 2114

Alfa AF: 0.0103 Hom.: 6

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

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

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
MetaRNN	Benign	0.0037	T
MetaSVM	Uncertain	-0.012	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		4.4
PrimateAI	Benign	0.25	T
PROVEAN	Uncertain	-4.2	D
REVEL	Uncertain	0.32
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.15
MPC		0.40
ClinPred		0.037	T
GERP RS		4.6
Varity_R		0.26
gMVP		0.42
Mutation Taster		=82/18	polymorphism (auto)

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