rs139468837

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr3-121772575-T-A
• chr3-121772575-T-C

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_001023570.4(IQCB1):​c.1549A>T​(p.Asn517Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.00238 in 1,614,226 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N517S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0023 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0024 (12 hom.)
• Consequence: IQCB1 NM_001023570.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:8
• Conservation: PhyloP100: 3.90
• 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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.020065188).
• BP6: Variant 3-121772575-T-A is Benign according to our data. Variant chr3-121772575-T-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 215481.
• BS2: High Homozygotes in GnomAd4 at 3 AD,AR gene

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.1549A>T	p.Asn517Tyr	missense	Exon 14 of 15	NP_001018864.2	Q15051-1
	IQCB1	NM_001319107.2		c.1549A>T	p.Asn517Tyr	missense	Exon 14 of 15	NP_001306036.1	Q15051-1
	IQCB1	NM_001023571.4		c.1150A>T	p.Asn384Tyr	missense	Exon 11 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.1549A>T	p.Asn517Tyr	missense	Exon 14 of 15	ENSP00000311505.6	Q15051-1
	IQCB1	ENST00000349820.10	TSL:1	c.1150A>T	p.Asn384Tyr	missense	Exon 11 of 12	ENSP00000323756.7	Q15051-2
	IQCB1	ENST00000923631.1		c.1621A>T	p.Asn541Tyr	missense	Exon 15 of 16	ENSP00000593690.1

Frequencies

GnomAD3 genomes AF: 0.00225 AC: 343 AN: 152222 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.000386

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00118

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000413

Gnomad FIN AF: 0.0136

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00234

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.00237 AC: 596 AN: 251432 AF XY: 0.00210

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.00142

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0116

Gnomad NFE exome AF: 0.00235

Gnomad OTH exome AF: 0.00179

GnomAD4 exome AF: 0.00239 AC: 3499 AN: 1461886 Hom.: 12 Cov.: 32 AF XY: 0.00233 AC XY: 1697 AN XY: 727244

African (AFR) AF: 0.000179 AC: 6 AN: 33480

American (AMR) AF: 0.00141 AC: 63 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0000765 AC: 2 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.000614 AC: 53 AN: 86258

European-Finnish (FIN) AF: 0.0118 AC: 630 AN: 53418

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.00235 AC: 2613 AN: 1112008

Other (OTH) AF: 0.00217 AC: 131 AN: 60396

GnomAD4 genome AF: 0.00225 AC: 343 AN: 152340 Hom.: 3 Cov.: 32 AF XY: 0.00268 AC XY: 200 AN XY: 74500

African (AFR) AF: 0.000385 AC: 16 AN: 41576

American (AMR) AF: 0.00118 AC: 18 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4834

European-Finnish (FIN) AF: 0.0136 AC: 144 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00234 AC: 159 AN: 68032

Other (OTH) AF: 0.00189 AC: 4 AN: 2116

Alfa AF: 0.00144 Hom.: 0

Bravo AF: 0.00131

TwinsUK AF: 0.00324 AC: 12

ALSPAC AF: 0.00182 AC: 7

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00233 AC: 20

ExAC AF: 0.00217 AC: 264

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	2	not specified (2)
-	-	1	IQCB1-related disorder (1)
-	-	1	Nephronophthisis (1)
-	1	-	Senior-Loken syndrome 5 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Uncertain	-0.080
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.22	T
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.83	T
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.020	T
MetaSVM	Uncertain	0.20	D
MutationAssessor	Uncertain	2.4	M
PhyloP100		3.9
PrimateAI	Uncertain	0.53	T
PROVEAN	Uncertain	-3.2	D
REVEL	Uncertain	0.43
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.011	D
Polyphen		0.99	D
Vest4		0.59
MVP		0.91
MPC		0.36
ClinPred		0.063	T
GERP RS		5.0
Varity_R		0.12
gMVP		0.19
Mutation Taster		=92/8	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: rs139468837; hg19: chr3-121491422;