rs33944211

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

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. 15/21 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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 0.254

Publications

22 publications found

Variant links:

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]

ARL13B links:

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]

DHFR2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId is 128452.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.117 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001174150.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ARL13B	NM_001174150.2	MANE Select	c.1043C>G	p.Thr348Ser	missense	Exon 8 of 10	NP_001167621.1
ARL13B	NM_182896.3		c.1043C>G	p.Thr348Ser	missense	Exon 8 of 11	NP_878899.1
ARL13B	NM_001321328.2		c.998C>G	p.Thr333Ser	missense	Exon 9 of 11	NP_001308257.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ARL13B	ENST00000394222.8	TSL:1 MANE Select	c.1043C>G	p.Thr348Ser	missense	Exon 8 of 10	ENSP00000377769.3
ARL13B	ENST00000471138.5	TSL:1	c.1043C>G	p.Thr348Ser	missense	Exon 8 of 11	ENSP00000420780.1
ARL13B	ENST00000535334.5	TSL:1	c.734C>G	p.Thr245Ser	missense	Exon 7 of 9	ENSP00000445145.1

Frequencies

GnomAD3 genomes

AF:

0.0815

AC:

12360

AN:

151572

Hom.:

627

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.0980

AC:

24218

AN:

247106

AF XY:

0.104

show subpopulations

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 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.:

AF XY:

0.109

AC XY:

78802

AN XY:

721102

show subpopulations

African (AFR)

AF:

0.0175

AC:

578

AN:

33028

American (AMR)

AF:

0.0628

AC:

2762

AN:

43962

Ashkenazi Jewish (ASJ)

AF:

0.134

AC:

3472

AN:

25856

East Asian (EAS)

AF:

0.0827

AC:

3263

AN:

39440

South Asian (SAS)

AF:

0.136

AC:

11441

AN:

84006

European-Finnish (FIN)

AF:

0.0964

AC:

5123

AN:

53130

Middle Eastern (MID)

AF:

0.150

AC:

861

AN:

5734

European-Non Finnish (NFE)

AF:

0.110

AC:

122052

AN:

1104644

Other (OTH)

AF:

0.114

AC:

6853

AN:

59890

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

5764

11528

17291

23055

28819

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

4354

8708

13062

17416

21770

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0814

AC:

12349

AN:

151688

Hom.:

626

Cov.:

AF XY:

0.0809

AC XY:

5993

AN XY:

74124

show subpopulations

African (AFR)

AF:

0.0198

AC:

819

AN:

41368

American (AMR)

AF:

0.0720

AC:

1097

AN:

15244

Ashkenazi Jewish (ASJ)

AF:

0.130

AC:

450

AN:

3460

East Asian (EAS)

AF:

0.0722

AC:

373

AN:

5166

South Asian (SAS)

AF:

0.126

AC:

604

AN:

4804

European-Finnish (FIN)

AF:

0.0987

AC:

1030

AN:

10440

Middle Eastern (MID)

AF:

0.192

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.113

AC:

7688

AN:

67906

Other (OTH)

AF:

0.0943

AC:

198

AN:

2100

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

556

1112

1668

2224

2780

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

150

300

450

600

750

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

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:

ESP6500EA

AF:

0.120

AC:

1033

ExAC

AF:

0.0985

AC:

11957

Asia WGS

AF:

0.0880

AC:

306

AN:

3476

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Joubert syndrome 8 (3)

not specified (3)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.092

BayesDel_addAF

Benign

-0.62

BayesDel_noAF

Benign

-0.55

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.050

Eigen

Benign

-0.19

Eigen_PC

Benign

-0.094

FATHMM_MKL

Benign

0.65

LIST_S2

Benign

0.66

MetaRNN

Benign

0.0016

MetaSVM

Benign

-0.95

MutationAssessor

Benign

0.60

PhyloP100

0.25

PrimateAI

Benign

0.40

PROVEAN

Benign

-0.020

REVEL

Benign

0.067

Sift

Benign

0.053

Sift4G

Benign

0.25

Polyphen

0.073

Vest4

0.12

MutPred

0.13

Gain of glycosylation at T348 (P = 0.0205)

MPC

0.067

ClinPred

0.0035

GERP RS

3.0

Varity_R

0.065

gMVP

0.12

Mutation Taster

=98/2

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over