Genetic Variant ARL13B:c.1025-3T>A (chr3-94049403-T-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001174150.2(ARL13B):c.1025-3T>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000841 in 1,545,670 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000072 ( 0 hom. )

Consequence

ARL13B
NM_001174150.2 splice_region, intron

Scores

Splicing: ADA: 0.0005431

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.403

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.6).

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	Effect	Exon Rank	Protein	UniProt
ARL13B	NM_001174150.2	MANE Select	c.1025-3T>A	splice_region intron	N/A	NP_001167621.1	Q3SXY8-1
ARL13B	NM_182896.3		c.1025-3T>A	splice_region intron	N/A	NP_878899.1	Q3SXY8-1
ARL13B	NM_001321328.2		c.980-3T>A	splice_region intron	N/A	NP_001308257.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
ARL13B	ENST00000394222.8	TSL:1 MANE Select	c.1025-3T>A	splice_region intron	N/A	ENSP00000377769.3	Q3SXY8-1
ARL13B	ENST00000471138.5	TSL:1	c.1025-3T>A	splice_region intron	N/A	ENSP00000420780.1	Q3SXY8-1
ARL13B	ENST00000535334.5	TSL:1	c.716-3T>A	splice_region intron	N/A	ENSP00000445145.1	Q3SXY8-3

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152052

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000246

AC:

AN:

244238

AF XY:

0.0000152

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000558

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000718

AC:

AN:

1393500

Hom.:

Cov.:

AF XY:

0.0000100

AC XY:

AN XY:

696660

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31668

American (AMR)

AF:

0.00

AC:

AN:

43334

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25448

East Asian (EAS)

AF:

0.00

AC:

AN:

39188

South Asian (SAS)

AF:

0.000110

AC:

AN:

82004

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53078

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5614

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1055168

Other (OTH)

AF:

0.0000172

AC:

AN:

57998

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.455

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152170

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74406

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41530

American (AMR)

AF:

0.00

AC:

AN:

15266

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.000193

AC:

AN:

5184

South Asian (SAS)

AF:

0.000414

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10576

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68002

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000113

Asia WGS

AF:

0.00318

AC:

AN:

3478

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

BayesDel_noAF

Benign

-0.60

CADD

Benign

(source)

DANN

Benign

0.61

PhyloP100

0.40

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00054

dbscSNV1_RF

Benign

0.29

SpliceAI score (max)

0.79

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.79

Position offset: -44

DS_AL_spliceai

0.57

Position offset: 3

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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