rs146264035

chr3-94050833-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The NM_001174150.2(ARL13B):c.1151G>A(p.Gly384Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00161 in 1,612,250 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0015 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0016 (8 hom.)
• Consequence: ARL13B NM_001174150.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:3
• Conservation: PhyloP100: 3.00

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]

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]

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.011502713).
• BP6: Variant 3-94050833-G-A is Benign according to our data. Variant chr3-94050833-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 346913.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=3}.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00148 (225/152170) while in subpopulation AMR AF= 0.00301 (46/15284). AF 95% confidence interval is 0.00232. There are 0 homozygotes in gnomad4. There are 110 alleles in male gnomad4 subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ARL13B	NM_001174150.2	c.1151G>A	p.Gly384Glu	missense_variant	9/10	ENST00000394222.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ARL13B	ENST00000394222.8	c.1151G>A	p.Gly384Glu	missense_variant	9/10	1	NM_001174150.2	P1

Frequencies

GnomAD3 genomes AF: 0.00149 AC: 226 AN: 152052 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.0242

Gnomad AMR AF: 0.00301

Gnomad ASJ AF: 0.00375

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.00160

Gnomad OTH AF: 0.00623

GnomAD3 exomes AF: 0.00137 AC: 344 AN: 250310 Hom.: 1 AF XY: 0.00139 AC XY: 188 AN XY: 135420

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.00153

Gnomad ASJ exome AF: 0.000993

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00167

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00189

Gnomad OTH exome AF: 0.00213

GnomAD4 exome AF: 0.00162 AC: 2368 AN: 1460080 Hom.: 8 Cov.: 30 AF XY: 0.00166 AC XY: 1203 AN XY: 726422

Gnomad4 AFR exome AF: 0.000448

Gnomad4 AMR exome AF: 0.00179

Gnomad4 ASJ exome AF: 0.00138

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00195

Gnomad4 FIN exome AF: 0.0000766

Gnomad4 NFE exome AF: 0.00171

Gnomad4 OTH exome AF: 0.00182

GnomAD4 genome AF: 0.00148 AC: 225 AN: 152170 Hom.: 0 Cov.: 32 AF XY: 0.00148 AC XY: 110 AN XY: 74396

Gnomad4 AFR AF: 0.000169

Gnomad4 AMR AF: 0.00301

Gnomad4 ASJ AF: 0.00375

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00160

Gnomad4 OTH AF: 0.00617

Alfa AF: 0.00193 Hom.: 2

Bravo AF: 0.00178

TwinsUK AF: 0.00162 AC: 6

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00186 AC: 16

ExAC AF: 0.00145 AC: 176

Asia WGS AF: 0.000289 AC: 1 AN: 3474

EpiCase AF: 0.00256

EpiControl AF: 0.00249

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Joubert syndrome 8 Uncertain:3 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 22, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Nov 20, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genomic Research Center, Shahid Beheshti University of Medical Sciences	Jan 01, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2020

This variant is associated with the following publications: (PMID: 25920555) -

ARL13B-related condition Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 08, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.38
Cadd	Benign	21
Dann	Uncertain	0.99
Eigen	Uncertain	0.22
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Benign	0.70	D
LIST_S2	Uncertain	0.87	D;D;.;D
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.012	T;T;T;T
MetaSVM	Benign	-0.65	T
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-1.7	N;N;N;N
REVEL	Benign	0.12
Sift	Benign	0.057	T;T;T;T
Sift4G	Benign	0.22	T;T;T;T
Polyphen		0.87, 0.13	.;P;B;B
Vest4		0.51
MVP		0.65
MPC		0.14
ClinPred		0.016	T
GERP RS		4.6
Varity_R		0.13
gMVP		0.18

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

LitVar

Other links and lift over

dbSNP: rs146264035; hg19: chr3-93769677;