chr3-121781850-G-A

Position:

chr3-121781850-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

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 (★★).

Frequency

Genomes: 𝑓 0.011 ( 17 hom., cov: 31)

Exomes 𝑓: 0.012 ( 247 hom. )

Consequence

IQCB1
NM_001023570.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 4.39

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 id is 219524.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-121781850-G-A is described in Lovd as [Benign].

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 male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 17 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IQCB1	NM_001023570.4 linkuse as main transcript	c.1303C>T	p.Arg435Cys	missense_variant	13/15	ENST00000310864.11	NP_001018864.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IQCB1	ENST00000310864.11 linkuse as main transcript	c.1303C>T	p.Arg435Cys	missense_variant	13/15	1	NM_001023570.4	ENSP00000311505	P1	Q15051-1
IQCB1	ENST00000349820.10 linkuse as main transcript	c.904C>T	p.Arg302Cys	missense_variant	10/12	1		ENSP00000323756		Q15051-2
IQCB1	ENST00000393650.7 linkuse as main transcript	c.*281C>T		3_prime_UTR_variant, NMD_transcript_variant	12/14	5		ENSP00000377261		Q15051-3

Frequencies

GnomAD3 genomes

AF:

0.0111

AC:

1680

AN:

151954

Hom.:

Cov.:

show subpopulations

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

GnomAD3 exomes

AF:

0.0139

AC:

3501

AN:

251390

Hom.:

AF XY:

0.0134

AC XY:

1814

AN XY:

135862

show subpopulations

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 SAS exome

AF:

0.000196

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.:

AF XY:

0.0115

AC XY:

8360

AN XY:

727042

show subpopulations

Gnomad4 AFR exome

AF:

0.00131

Gnomad4 AMR exome

AF:

0.000895

Gnomad4 ASJ exome

AF:

0.000345

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000220

Gnomad4 FIN exome

AF:

0.0615

Gnomad4 NFE exome

AF:

0.0122

Gnomad4 OTH exome

AF:

0.00963

GnomAD4 genome

AF:

0.0110

AC:

1679

AN:

152074

Hom.:

Cov.:

AF XY:

0.0128

AC XY:

952

AN XY:

74310

show subpopulations

Gnomad4 AFR

AF:

0.00137

Gnomad4 AMR

AF:

0.00157

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.000208

Gnomad4 FIN

AF:

0.0664

Gnomad4 NFE

AF:

0.0129

Gnomad4 OTH

AF:

0.00851

Alfa

AF:

0.0106

Hom.:

Bravo

AF:

0.00609

TwinsUK

AF:

0.0121

AC:

ALSPAC

AF:

0.0104

AC:

ESP6500AA

AF:

0.00272

AC:

ESP6500EA

AF:

0.0149

AC:

128

ExAC

AF:

0.0156

AC:

1896

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 31, 2020	- -

Senior-Loken syndrome 5

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Nephronophthisis

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.19

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.34

T;.

Eigen

Uncertain

0.38

Eigen_PC

Uncertain

0.29

FATHMM_MKL

Uncertain

0.78

LIST_S2

Uncertain

0.89

D;D

MetaRNN

Benign

0.0037

T;T

MetaSVM

Uncertain

-0.012

MutationAssessor

Uncertain

2.4

M;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Benign

0.25

PROVEAN

Uncertain

-4.2

D;D

REVEL

Uncertain

0.32

Sift

Uncertain

0.0010

D;D

Sift4G

Uncertain

0.0020

D;D

Polyphen

1.0

D;D

Vest4

0.15

MPC

0.40

ClinPred

0.037

GERP RS

4.6

Varity_R

0.26

gMVP

0.42

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over