chr3-121770148-C-G

Variant names:

• chr3-121770148-C-G
• rs1135750
• NM_001023570.4:c.*197G>C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001023570.4(IQCB1):​c.*197G>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.619 in 563,820 control chromosomes in the GnomAD database, including 110,383 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.64 (31987 hom., cov: 32)
  • Exomes 𝑓: 0.61 (78396 hom.)
• Consequence: IQCB1 NM_001023570.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.162

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 3-121770148-C-G is Benign according to our data. Variant chr3-121770148-C-G is described in ClinVar as [Benign]. Clinvar id is 342768.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.708 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IQCB1	NM_001023570.4	c.*197G>C		3_prime_UTR_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	c.*197G>C		3_prime_UTR_variant	Exon 15 of 15	1	NM_001023570.4	ENSP00000311505.6
IQCB1	ENST00000349820	c.*197G>C		3_prime_UTR_variant	Exon 12 of 12	1		ENSP00000323756.7
IQCB1	ENST00000393650.7	n.*972G>C		non_coding_transcript_exon_variant	Exon 14 of 14	5		ENSP00000377261.3
IQCB1	ENST00000393650.7	n.*972G>C		3_prime_UTR_variant	Exon 14 of 14	5		ENSP00000377261.3

Frequencies

GnomAD3 genomes AF: 0.644 AC: 97819 AN: 151922 Hom.: 31955 Cov.: 32

Gnomad AFR AF: 0.715

Gnomad AMI AF: 0.680

Gnomad AMR AF: 0.664

Gnomad ASJ AF: 0.554

Gnomad EAS AF: 0.319

Gnomad SAS AF: 0.660

Gnomad FIN AF: 0.663

Gnomad MID AF: 0.554

Gnomad NFE AF: 0.622

Gnomad OTH AF: 0.631

GnomAD4 exome AF: 0.610 AC: 251056 AN: 411780 Hom.: 78396 Cov.: 3 AF XY: 0.611 AC XY: 132507 AN XY: 217012

Gnomad4 AFR exome AF: 0.714

Gnomad4 AMR exome AF: 0.716

Gnomad4 ASJ exome AF: 0.561

Gnomad4 EAS exome AF: 0.323

Gnomad4 SAS exome AF: 0.655

Gnomad4 FIN exome AF: 0.668

Gnomad4 NFE exome AF: 0.620

Gnomad4 OTH exome AF: 0.605

GnomAD4 genome AF: 0.644 AC: 97902 AN: 152040 Hom.: 31987 Cov.: 32 AF XY: 0.645 AC XY: 47951 AN XY: 74330

Gnomad4 AFR AF: 0.715

Gnomad4 AMR AF: 0.665

Gnomad4 ASJ AF: 0.554

Gnomad4 EAS AF: 0.319

Gnomad4 SAS AF: 0.659

Gnomad4 FIN AF: 0.663

Gnomad4 NFE AF: 0.622

Gnomad4 OTH AF: 0.630

Alfa AF: 0.503 Hom.: 1332

Bravo AF: 0.641

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nov 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Senior-Loken syndrome 5 Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	1.2
DANN	Benign	0.37

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: rs1135750; hg19: chr3-121488995; COSMIC: COSV60436121;