chr3-121772575-T-C

Variant names:

• chr3-121772575-T-C
• rs139468837
• NM_001023570.4:c.1549A>G

Variant summary

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

The NM_001023570.4(IQCB1):​c.1549A>G​(p.Asn517Asp) variant causes a missense change. The variant allele was found at a frequency of 0.0000131 in 152,226 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N517Y) has been classified as Likely benign.

• Frequency: Genomes: 𝑓 0.000013 (0 hom., cov: 32)
• Consequence: IQCB1 NM_001023570.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.90

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=0.15485728).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IQCB1	NM_001023570.4	c.1549A>G	p.Asn517Asp	missense_variant	Exon 14 of 15	ENST00000310864.11	NP_001018864.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IQCB1	ENST00000310864.11	c.1549A>G	p.Asn517Asp	missense_variant	Exon 14 of 15	1	NM_001023570.4	ENSP00000311505.6
IQCB1	ENST00000349820.10	c.1150A>G	p.Asn384Asp	missense_variant	Exon 11 of 12	1		ENSP00000323756.7
IQCB1	ENST00000393650.7	n.*527A>G		non_coding_transcript_exon_variant	Exon 13 of 14	5		ENSP00000377261.3
IQCB1	ENST00000393650.7	n.*527A>G		3_prime_UTR_variant	Exon 13 of 14	5		ENSP00000377261.3

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152226 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 32

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152226 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74376

Gnomad4 AFR AF: 0.0000482

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Nephronophthisis Uncertain:1

Feb 24, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces asparagine, which is neutral and polar, with aspartic acid, which is acidic and polar, at codon 517 of the IQCB1 protein (p.Asn517Asp). This variant is present in population databases (no rsID available, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with IQCB1-related conditions. ClinVar contains an entry for this variant (Variation ID: 954309). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt IQCB1 protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.064	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	19
DANN	Benign	0.77
DEOGEN2	Benign	0.031	T;.
Eigen	Benign	-0.17
Eigen_PC	Benign	-0.081
FATHMM_MKL	Benign	0.70	D
LIST_S2	Benign	0.77	T;T
M_CAP	Benign	0.057	D
MetaRNN	Benign	0.15	T;T
MetaSVM	Benign	-0.61	T
MutationAssessor	Benign	1.4	L;.
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	1.2	N;N
REVEL	Benign	0.23
Sift	Benign	1.0	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.96	P;B
Vest4		0.22
MutPred		0.27		Loss of helix (P = 0.0444);.;
MVP		0.85
MPC		0.14
ClinPred		0.38	T
GERP RS		5.0
Varity_R		0.054
gMVP		0.077

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: rs139468837; hg19: chr3-121491422;