rs146396078

chr3-93995919-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001174150.2(ARL13B):c.105C>T(p.Thr35=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.008 in 1,613,128 control chromosomes in the GnomAD database, including 87 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0071 (6 hom., cov: 32)
  • Exomes 𝑓: 0.0081 (81 hom.)
• Consequence: ARL13B NM_001174150.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -1.91

Genes affected

ARL13B (HGNC:25419): (ADP ribosylation factor like GTPase 13B) This gene encodes a member of the ADP-ribosylation factor-like family. The encoded protein is a small GTPase that contains both N-terminal and C-terminal guanine nucleotide-binding motifs. This protein is localized in the cilia and plays a role in cilia formation and in maintenance of cilia. Mutations in this gene are the cause of Joubert syndrome 8. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Mar 2010]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.69).
• BP6: Variant 3-93995919-C-T is Benign according to our data. Variant chr3-93995919-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 128453.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-93995919-C-T is described in Lovd as [Likely_benign]. Variant chr3-93995919-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-1.91 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00714 (1087/152204) while in subpopulation NFE AF= 0.00947 (644/68004). AF 95% confidence interval is 0.00886. There are 6 homozygotes in gnomad4. There are 484 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ARL13B	NM_001174150.2	c.105C>T	p.Thr35=	synonymous_variant	2/10	ENST00000394222.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ARL13B	ENST00000394222.8	c.105C>T	p.Thr35=	synonymous_variant	2/10	1	NM_001174150.2	P1

Frequencies

GnomAD3 genomes AF: 0.00717 AC: 1090 AN: 152088 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.00183

Gnomad AMI AF: 0.0198

Gnomad AMR AF: 0.00839

Gnomad ASJ AF: 0.0435

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.00151

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.00947

Gnomad OTH AF: 0.0182

GnomAD3 exomes AF: 0.00796 AC: 1997 AN: 250734 Hom.: 22 AF XY: 0.00831 AC XY: 1127 AN XY: 135596

Gnomad AFR exome AF: 0.00117

Gnomad AMR exome AF: 0.00718

Gnomad ASJ exome AF: 0.0417

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00337

Gnomad FIN exome AF: 0.00143

Gnomad NFE exome AF: 0.00954

Gnomad OTH exome AF: 0.0157

GnomAD4 exome AF: 0.00809 AC: 11824 AN: 1460924 Hom.: 81 Cov.: 31 AF XY: 0.00806 AC XY: 5861 AN XY: 726772

Gnomad4 AFR exome AF: 0.00164

Gnomad4 AMR exome AF: 0.00749

Gnomad4 ASJ exome AF: 0.0406

Gnomad4 EAS exome AF: 0.0000505

Gnomad4 SAS exome AF: 0.00312

Gnomad4 FIN exome AF: 0.00131

Gnomad4 NFE exome AF: 0.00829

Gnomad4 OTH exome AF: 0.0103

GnomAD4 genome AF: 0.00714 AC: 1087 AN: 152204 Hom.: 6 Cov.: 32 AF XY: 0.00651 AC XY: 484 AN XY: 74392

Gnomad4 AFR AF: 0.00183

Gnomad4 AMR AF: 0.00831

Gnomad4 ASJ AF: 0.0435

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00166

Gnomad4 FIN AF: 0.00151

Gnomad4 NFE AF: 0.00947

Gnomad4 OTH AF: 0.0180

Alfa AF: 0.00982 Hom.: 7

Bravo AF: 0.00785

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.0135

EpiControl AF: 0.0116

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 06, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	May 29, 2015	- -

Joubert syndrome 8 Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Jun 28, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Dec 01, 2014	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
Cadd	Benign	2.5
Dann	Benign	0.66

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs146396078; hg19: chr3-93714763;