rs146396078

Variant names:

• chr3-93995919-C-T
• rs146396078
• NM_001174150.2:c.105C>T

Your query was ambiguous. Multiple possible variants found:

• chr3-93995919-C-T
• chr3-93995919-C-A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001321328.2(ARL13B):​c.-63C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.008 in 1,613,128 control chromosomes in the GnomAD database, including 87 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0071 (6 hom., cov: 32)
  • Exomes 𝑓: 0.0081 (81 hom.)
• Consequence: ARL13B NM_001321328.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -1.91
• Publications: 6 publications found

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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.69).
• BP6: Variant 3-93995919-C-T is Benign according to our data. Variant chr3-93995919-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 128453.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00714 (1087/152204) while in subpopulation NFE AF = 0.00947 (644/68004). AF 95% confidence interval is 0.00886. There are 6 homozygotes in GnomAd4. There are 484 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 6 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001321328.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARL13B	NM_001174150.2	MANE Select	c.105C>T	p.Thr35Thr	synonymous	Exon 2 of 10	NP_001167621.1	Q3SXY8-1
	ARL13B	NM_001321328.2		c.-63C>T		5_prime_UTR_premature_start_codon_gain	Exon 2 of 11	NP_001308257.1
	ARL13B	NM_182896.3		c.105C>T	p.Thr35Thr	synonymous	Exon 2 of 11	NP_878899.1	Q3SXY8-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARL13B	ENST00000394222.8	TSL:1 MANE Select	c.105C>T	p.Thr35Thr	synonymous	Exon 2 of 10	ENSP00000377769.3	Q3SXY8-1
	ARL13B	ENST00000471138.5	TSL:1	c.105C>T	p.Thr35Thr	synonymous	Exon 2 of 11	ENSP00000420780.1	Q3SXY8-1
	ARL13B	ENST00000535334.5	TSL:1	c.-179-7740C>T		intron	N/A	ENSP00000445145.1	Q3SXY8-3

Frequencies

GnomAD3 genomes AF: 0.00717 AC: 1090 AN: 152088 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.00183

Gnomad AMI AF: 0.0198

Gnomad AMR AF: 0.00839

Gnomad ASJ AF: 0.0435

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.00151

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.00947

Gnomad OTH AF: 0.0182

GnomAD2 exomes AF: 0.00796 AC: 1997 AN: 250734 AF XY: 0.00831

Gnomad AFR exome AF: 0.00117

Gnomad AMR exome AF: 0.00718

Gnomad ASJ exome AF: 0.0417

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00143

Gnomad NFE exome AF: 0.00954

Gnomad OTH exome AF: 0.0157

GnomAD4 exome AF: 0.00809 AC: 11824 AN: 1460924 Hom.: 81 Cov.: 31 AF XY: 0.00806 AC XY: 5861 AN XY: 726772

African (AFR) AF: 0.00164 AC: 55 AN: 33438

American (AMR) AF: 0.00749 AC: 335 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.0406 AC: 1060 AN: 26116

East Asian (EAS) AF: 0.0000505 AC: 2 AN: 39616

South Asian (SAS) AF: 0.00312 AC: 269 AN: 86140

European-Finnish (FIN) AF: 0.00131 AC: 70 AN: 53378

Middle Eastern (MID) AF: 0.0347 AC: 200 AN: 5758

European-Non Finnish (NFE) AF: 0.00829 AC: 9211 AN: 1111438

Other (OTH) AF: 0.0103 AC: 622 AN: 60332

GnomAD4 genome AF: 0.00714 AC: 1087 AN: 152204 Hom.: 6 Cov.: 32 AF XY: 0.00651 AC XY: 484 AN XY: 74392

African (AFR) AF: 0.00183 AC: 76 AN: 41546

American (AMR) AF: 0.00831 AC: 127 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.0435 AC: 151 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00166 AC: 8 AN: 4826

European-Finnish (FIN) AF: 0.00151 AC: 16 AN: 10586

Middle Eastern (MID) AF: 0.0306 AC: 9 AN: 294

European-Non Finnish (NFE) AF: 0.00947 AC: 644 AN: 68004

Other (OTH) AF: 0.0180 AC: 38 AN: 2112

Alfa AF: 0.00905 Hom.: 9

Bravo AF: 0.00785

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.0135

EpiControl AF: 0.0116

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Joubert syndrome 8 (3)
-	-	3	not specified (3)
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
CADD	Benign	2.5
DANN	Benign	0.66
PhyloP100		-1.9
Mutation Taster		=296/4	polymorphism

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

Other links and lift over

dbSNP: rs146396078; hg19: chr3-93714763;