dbSNP rs863225149: ARL13B:p.Val22Gly (chr3-93995879-T-G) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2PP3_ModeratePP5_Moderate

The NM_001174150.2(ARL13B):c.65T>G(p.Val22Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V22M) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

ARL13B
NM_001174150.2 missense

Scores

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 7.99

Publications

1 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 Gene-Disease associations (from GenCC):

Joubert syndrome
Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
Joubert syndrome 8
Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics

ARL13B links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.847

PP5

Variant 3-93995879-T-G is Pathogenic according to our data. Variant chr3-93995879-T-G is described in ClinVar as Pathogenic. ClinVar VariationId is 217551.Status of the report is criteria_provided_single_submitter, 1 stars.

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	UniProt
ARL13B	NM_001174150.2	MANE Select	c.65T>G	p.Val22Gly	missense	Exon 2 of 10	NP_001167621.1	Q3SXY8-1
ARL13B	NM_182896.3		c.65T>G	p.Val22Gly	missense	Exon 2 of 11	NP_878899.1	Q3SXY8-1
ARL13B	NM_001410782.1		c.65T>G	p.Val22Gly	missense	Exon 2 of 9	NP_001397711.1	A0A7P0Z473

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ARL13B	ENST00000394222.8	TSL:1 MANE Select	c.65T>G	p.Val22Gly	missense	Exon 2 of 10	ENSP00000377769.3	Q3SXY8-1
ARL13B	ENST00000471138.5	TSL:1	c.65T>G	p.Val22Gly	missense	Exon 2 of 11	ENSP00000420780.1	Q3SXY8-1
ARL13B	ENST00000535334.5	TSL:1	c.-179-7780T>G		intron	N/A	ENSP00000445145.1	Q3SXY8-3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Pathogenic

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Joubert syndrome 8 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.86

BayesDel_addAF

Pathogenic

0.39

BayesDel_noAF

Pathogenic

0.32

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.60

Eigen

Pathogenic

0.71

Eigen_PC

Pathogenic

0.73

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.85

M_CAP

Uncertain

0.19

MetaRNN

Pathogenic

0.85

MetaSVM

Uncertain

0.088

MutationAssessor

Benign

1.9

PhyloP100

8.0

PrimateAI

Uncertain

0.62

PROVEAN

Pathogenic

-5.7

REVEL

Pathogenic

0.85

Sift

Uncertain

0.0010

Sift4G

Pathogenic

0.0010

Polyphen

0.97

Vest4

0.86

MutPred

0.62

Loss of stability (P = 0.0254)

MVP

0.92

MPC

0.49

ClinPred

1.0

GERP RS

5.6

Varity_R

0.97

gMVP

0.91

Mutation Taster

=67/233

disease causing (ClinVar)

(source)

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

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over