3-121770439-A-G

Variant names:

• chr3-121770439-A-G
• rs145400780
• NM_001023570.4:c.1703T>C

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 1P and 9B. PP3 BP4_Strong BP6 BS1

The NM_001023570.4(IQCB1):​c.1703T>C​(p.Leu568Pro) variant causes a missense change. The variant allele was found at a frequency of 0.000269 in 1,614,184 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00016 (0 hom.)
• Consequence: IQCB1 NM_001023570.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 6.57
• Publications: 4 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 -8 ACMG points.

• PP3: Multiple lines of computational evidence support a deleterious effect 7: BayesDel_noAF, Cadd, Dann, Eigen, PROVEAN, REVEL, REVEL [when BayesDel_addAF, max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.0652425).
• BP6: Variant 3-121770439-A-G is Benign according to our data. Variant chr3-121770439-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 695529.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00131 (200/152308) while in subpopulation AFR AF = 0.00467 (194/41560). AF 95% confidence interval is 0.00413. There are 0 homozygotes in GnomAd4. There are 84 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

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.1703T>C	p.Leu568Pro	missense	Exon 15 of 15	NP_001018864.2	Q15051-1
	IQCB1	NM_001319107.2		c.1703T>C	p.Leu568Pro	missense	Exon 15 of 15	NP_001306036.1	Q15051-1
	IQCB1	NM_001023571.4		c.1304T>C	p.Leu435Pro	missense	Exon 12 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.1703T>C	p.Leu568Pro	missense	Exon 15 of 15	ENSP00000311505.6	Q15051-1
	IQCB1	ENST00000349820.10	TSL:1	c.1304T>C	p.Leu435Pro	missense	Exon 12 of 12	ENSP00000323756.7	Q15051-2
	IQCB1	ENST00000923631.1		c.1775T>C	p.Leu592Pro	missense	Exon 16 of 16	ENSP00000593690.1

Frequencies

GnomAD3 genomes AF: 0.00132 AC: 201 AN: 152190 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00468

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000955

GnomAD2 exomes AF: 0.000362 AC: 91 AN: 251422 AF XY: 0.000258

Gnomad AFR exome AF: 0.00523

Gnomad AMR exome AF: 0.000116

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: 0.00

GnomAD4 exome AF: 0.000160 AC: 234 AN: 1461876 Hom.: 0 Cov.: 31 AF XY: 0.000146 AC XY: 106 AN XY: 727246

African (AFR) AF: 0.00591 AC: 198 AN: 33476

American (AMR) AF: 0.000134 AC: 6 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000117 AC: 13 AN: 1112000

Other (OTH) AF: 0.000265 AC: 16 AN: 60396

GnomAD4 genome AF: 0.00131 AC: 200 AN: 152308 Hom.: 0 Cov.: 32 AF XY: 0.00113 AC XY: 84 AN XY: 74472

African (AFR) AF: 0.00467 AC: 194 AN: 41560

American (AMR) AF: 0.000131 AC: 2 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68026

Other (OTH) AF: 0.000945 AC: 2 AN: 2116

Alfa AF: 0.000574 Hom.: 2

Bravo AF: 0.00179

ESP6500AA AF: 0.00522 AC: 23

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000420 AC: 51

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	not provided (2)
-	-	1	IQCB1-related disorder (1)
-	-	1	Nephronophthisis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.55
BayesDel_addAF	Benign	-0.057	T
BayesDel_noAF	Pathogenic	0.15
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.34	T
Eigen	Pathogenic	0.69
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.80	T
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.065	T
MetaSVM	Uncertain	0.18	D
MutationAssessor	Uncertain	2.6	M
PhyloP100		6.6
PrimateAI	Uncertain	0.65	T
PROVEAN	Uncertain	-4.3	D
REVEL	Pathogenic	0.74
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0020	D
Polyphen		0.99	D
Vest4		0.92
MVP		0.96
MPC		0.52
ClinPred		0.10	T
GERP RS		5.5
Varity_R		0.86
gMVP		0.77
Mutation Taster		=71/29	polymorphism

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: rs145400780; hg19: chr3-121489286;