rs11554412

chr3-94050868-C-Gchr3-94050868-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001174150.2(ARL13B):c.1186C>G(p.Pro396Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00716 in 1,612,916 control chromosomes in the GnomAD database, including 50 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0052 (8 hom., cov: 32)
  • Exomes 𝑓: 0.0074 (42 hom.)
• Consequence: ARL13B NM_001174150.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 2.16

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=0.008797377).
• BP6: Variant 3-94050868-C-G is Benign according to our data. Variant chr3-94050868-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 199197.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-94050868-C-G is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0052 (792/152194) while in subpopulation NFE AF= 0.00822 (559/67994). AF 95% confidence interval is 0.00766. There are 8 homozygotes in gnomad4. There are 364 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ARL13B	NM_001174150.2	c.1186C>G	p.Pro396Ala	missense_variant	9/10	ENST00000394222.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ARL13B	ENST00000394222.8	c.1186C>G	p.Pro396Ala	missense_variant	9/10	1	NM_001174150.2	P1

Frequencies

GnomAD3 genomes AF: 0.00522 AC: 794 AN: 152076 Hom.: 8 Cov.: 32

Gnomad AFR AF: 0.00133

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00583

Gnomad ASJ AF: 0.00490

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00373

Gnomad FIN AF: 0.00359

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00822

Gnomad OTH AF: 0.00767

GnomAD3 exomes AF: 0.00605 AC: 1518 AN: 250934 Hom.: 7 AF XY: 0.00616 AC XY: 836 AN XY: 135678

Gnomad AFR exome AF: 0.00117

Gnomad AMR exome AF: 0.00500

Gnomad ASJ exome AF: 0.00387

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00376

Gnomad FIN exome AF: 0.00404

Gnomad NFE exome AF: 0.00917

Gnomad OTH exome AF: 0.00719

GnomAD4 exome AF: 0.00737 AC: 10764 AN: 1460722 Hom.: 42 Cov.: 30 AF XY: 0.00726 AC XY: 5276 AN XY: 726684

Gnomad4 AFR exome AF: 0.00129

Gnomad4 AMR exome AF: 0.00497

Gnomad4 ASJ exome AF: 0.00452

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00399

Gnomad4 FIN exome AF: 0.00513

Gnomad4 NFE exome AF: 0.00840

Gnomad4 OTH exome AF: 0.00648

GnomAD4 genome AF: 0.00520 AC: 792 AN: 152194 Hom.: 8 Cov.: 32 AF XY: 0.00489 AC XY: 364 AN XY: 74416

Gnomad4 AFR AF: 0.00132

Gnomad4 AMR AF: 0.00582

Gnomad4 ASJ AF: 0.00490

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00353

Gnomad4 FIN AF: 0.00359

Gnomad4 NFE AF: 0.00822

Gnomad4 OTH AF: 0.00759

Alfa AF: 0.00693 Hom.: 0

Bravo AF: 0.00519

TwinsUK AF: 0.0121 AC: 45

ALSPAC AF: 0.00752 AC: 29

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00814 AC: 70

ExAC AF: 0.00647 AC: 785

Asia WGS AF: 0.00231 AC: 8 AN: 3476

EpiCase AF: 0.00714

EpiControl AF: 0.00842

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 29, 2014	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 08, 2016	- -

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jul 19, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	ARL13B: BP4, BS2 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 14, 2019	- -

Joubert syndrome 8 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Joubert syndrome 1 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.23
Cadd	Benign	22
Dann	Uncertain	0.99
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.79	T;T;.;T
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.0088	T;T;T;T
MetaSVM	Uncertain	-0.10	T
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Benign	0.42	T
PROVEAN	Uncertain	-2.5	D;N;N;N
REVEL	Benign	0.20
Sift	Uncertain	0.010	D;D;D;D
Sift4G	Benign	0.24	T;T;T;T
Polyphen		1.0, 0.95	.;D;P;P
Vest4		0.40
MVP		0.83
MPC		0.077
ClinPred		0.030	T
GERP RS		5.5
Varity_R		0.065
gMVP		0.27

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: rs11554412; hg19: chr3-93769712;