rs33944211

chr3-94049424-C-G

Variant summary

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

The NM_001174150.2(ARL13B):c.1043C>G(p.Thr348Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.105 in 1,601,378 control chromosomes in the GnomAD database, including 9,697 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.081 (626 hom., cov: 31)
  • Exomes 𝑓: 0.11 (9071 hom.)
• Consequence: ARL13B NM_001174150.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.254

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]

DHFR2 (HGNC:27309): (dihydrofolate reductase 2) Enables dihydrofolate reductase activity and mRNA binding activity. Involved in tetrahydrofolate metabolic process and thymidine biosynthetic process. Located in mitochondrial inner membrane and mitochondrial matrix. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0016124547).
• BP6: Variant 3-94049424-C-G is Benign according to our data. Variant chr3-94049424-C-G is described in ClinVar as [Benign]. Clinvar id is 128452.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-94049424-C-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.117 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ARL13B	NM_001174150.2	c.1043C>G	p.Thr348Ser	missense_variant	8/10	ENST00000394222.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ARL13B	ENST00000394222.8	c.1043C>G	p.Thr348Ser	missense_variant	8/10	1	NM_001174150.2	P1

Frequencies

GnomAD3 genomes AF: 0.0815 AC: 12360 AN: 151572 Hom.: 627 Cov.: 31

Gnomad AFR AF: 0.0199

Gnomad AMI AF: 0.0374

Gnomad AMR AF: 0.0719

Gnomad ASJ AF: 0.130

Gnomad EAS AF: 0.0722

Gnomad SAS AF: 0.126

Gnomad FIN AF: 0.0987

Gnomad MID AF: 0.197

Gnomad NFE AF: 0.113

Gnomad OTH AF: 0.0948

GnomAD3 exomes AF: 0.0980 AC: 24218 AN: 247106 Hom.: 1388 AF XY: 0.104 AC XY: 13880 AN XY: 133542

Gnomad AFR exome AF: 0.0188

Gnomad AMR exome AF: 0.0592

Gnomad ASJ exome AF: 0.137

Gnomad EAS exome AF: 0.0718

Gnomad SAS exome AF: 0.137

Gnomad FIN exome AF: 0.0964

Gnomad NFE exome AF: 0.111

Gnomad OTH exome AF: 0.110

GnomAD4 exome AF: 0.108 AC: 156405 AN: 1449690 Hom.: 9071 Cov.: 29 AF XY: 0.109 AC XY: 78802 AN XY: 721102

Gnomad4 AFR exome AF: 0.0175

Gnomad4 AMR exome AF: 0.0628

Gnomad4 ASJ exome AF: 0.134

Gnomad4 EAS exome AF: 0.0827

Gnomad4 SAS exome AF: 0.136

Gnomad4 FIN exome AF: 0.0964

Gnomad4 NFE exome AF: 0.110

Gnomad4 OTH exome AF: 0.114

GnomAD4 genome AF: 0.0814 AC: 12349 AN: 151688 Hom.: 626 Cov.: 31 AF XY: 0.0809 AC XY: 5993 AN XY: 74124

Gnomad4 AFR AF: 0.0198

Gnomad4 AMR AF: 0.0720

Gnomad4 ASJ AF: 0.130

Gnomad4 EAS AF: 0.0722

Gnomad4 SAS AF: 0.126

Gnomad4 FIN AF: 0.0987

Gnomad4 NFE AF: 0.113

Gnomad4 OTH AF: 0.0943

Alfa AF: 0.109 Hom.: 361

Bravo AF: 0.0749

TwinsUK AF: 0.107 AC: 396

ALSPAC AF: 0.111 AC: 427

ESP6500AA AF: 0.0222 AC: 98

ESP6500EA AF: 0.120 AC: 1033

ExAC AF: 0.0985 AC: 11957

Asia WGS AF: 0.0880 AC: 306 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 02, 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. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Joubert syndrome 8 Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	May 31, 2017	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.55
Cadd	Benign	15
Dann	Benign	0.97
Eigen	Benign	-0.19
Eigen_PC	Benign	-0.094
FATHMM_MKL	Benign	0.65	D
LIST_S2	Benign	0.66	T;T;.;T
MetaRNN	Benign	0.0016	T;T;T;T
MetaSVM	Benign	-0.95	T
MutationTaster	Benign	0.99	P;P;P;P;P
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.020	N;N;N;N
REVEL	Benign	0.067
Sift	Benign	0.053	T;D;T;T
Sift4G	Benign	0.25	T;T;T;T
Polyphen		0.073, 0.012	.;B;B;B
Vest4		0.12
MutPred		0.13		.;.;Gain of glycosylation at T348 (P = 0.0205);Gain of glycosylation at T348 (P = 0.0205);
MPC		0.067
ClinPred		0.0035	T
GERP RS		3.0
Varity_R		0.065
gMVP		0.12

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs33944211; hg19: chr3-93768268; COSMIC: COSV57398325;