Genetic Variant ARL13B:p.His357Tyr (chr3-94049450-C-T) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_001174150.2(ARL13B):c.1069C>T(p.His357Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H357R) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 31)

Consequence

ARL13B
NM_001174150.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.86

Publications

0 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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.41856882).

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.1069C>T	p.His357Tyr	missense	Exon 8 of 10	NP_001167621.1	Q3SXY8-1
ARL13B	NM_182896.3		c.1069C>T	p.His357Tyr	missense	Exon 8 of 11	NP_878899.1	Q3SXY8-1
ARL13B	NM_001321328.2		c.1024C>T	p.His342Tyr	missense	Exon 9 of 11	NP_001308257.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ARL13B	ENST00000394222.8	TSL:1 MANE Select	c.1069C>T	p.His357Tyr	missense	Exon 8 of 10	ENSP00000377769.3	Q3SXY8-1
ARL13B	ENST00000471138.5	TSL:1	c.1069C>T	p.His357Tyr	missense	Exon 8 of 11	ENSP00000420780.1	Q3SXY8-1
ARL13B	ENST00000535334.5	TSL:1	c.760C>T	p.His254Tyr	missense	Exon 7 of 9	ENSP00000445145.1	Q3SXY8-3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

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

Benign

0.17

BayesDel_addAF

Benign

-0.058

BayesDel_noAF

Benign

-0.32

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.22

Eigen

Uncertain

0.26

Eigen_PC

Uncertain

0.30

FATHMM_MKL

Benign

0.75

LIST_S2

Uncertain

0.91

M_CAP

Benign

0.023

MetaRNN

Benign

0.42

MetaSVM

Benign

-0.46

MutationAssessor

Benign

1.3

PhyloP100

1.9

PrimateAI

Uncertain

0.54

PROVEAN

Benign

-2.0

REVEL

Benign

0.11

Sift

Uncertain

0.0030

Sift4G

Benign

0.18

Polyphen

0.73

Vest4

0.60

MutPred

0.32

Gain of loop (P = 0.0079)

MVP

0.67

MPC

0.24

ClinPred

0.91

GERP RS

3.2

Varity_R

0.23

gMVP

0.32

Mutation Taster

=74/26

polymorphism

(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