3-121770383-A-T

Variant names:

• chr3-121770383-A-T
• NM_001023570.4:c.1759T>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001023570.4(IQCB1):​c.1759T>A​(p.Leu587Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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 Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: IQCB1 NM_001023570.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.40

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.22024783).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IQCB1	NM_001023570.4	c.1759T>A	p.Leu587Ile	missense_variant	Exon 15 of 15	ENST00000310864.11	NP_001018864.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IQCB1	ENST00000310864.11	c.1759T>A	p.Leu587Ile	missense_variant	Exon 15 of 15	1	NM_001023570.4	ENSP00000311505.6
IQCB1	ENST00000349820.10	c.1360T>A	p.Leu454Ile	missense_variant	Exon 12 of 12	1		ENSP00000323756.7
IQCB1	ENST00000393650.7	n.*737T>A		non_coding_transcript_exon_variant	Exon 14 of 14	5		ENSP00000377261.3
IQCB1	ENST00000393650.7	n.*737T>A		3_prime_UTR_variant	Exon 14 of 14	5		ENSP00000377261.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Senior-Loken syndrome 5 Uncertain:1

-

Neuberg Centre For Genomic Medicine, NCGM

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The observed missense variant c.1759T>A(p.Leu587Ile) in IQCB1 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. This variant is absent in gnomAD Exomes. The amino acid Leu at position 587 is changed to a Ile changing protein sequence and it might alter its composition and physico-chemical properties. Computational evidence (Polyphen-probably damaging, SIFT-Tolerated and MutationTaster-Disease causing) predicts conflicting evidence on protein structure and function for this variant. The reference amino acid p.Leu587Ile in IQCB1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.029	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.025	T;.
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.76	T;T
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.22	T;T
MetaSVM	Benign	-0.80	T
MutationAssessor	Uncertain	2.6	M;.
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-0.47	N;N
REVEL	Benign	0.20
Sift	Benign	0.18	T;T
Sift4G	Benign	0.22	T;D
Polyphen		0.99	D;D
Vest4		0.31
MutPred		0.56		Gain of sheet (P = 0.0266);.;
MVP		0.56
MPC		0.093
ClinPred		0.57	D
GERP RS		5.5
Varity_R		0.076
gMVP		0.17

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr3-121489230;