3-94049426-A-G

Position:

• chr3-94049426-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001174150.2(ARL13B):​c.1045A>G​(p.Lys349Glu) variant causes a missense change. The variant allele was found at a frequency of 0.000672 in 1,606,368 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00048 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00069 (3 hom.)
• Consequence: ARL13B NM_001174150.2 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 4.43

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.02589494).
• BP6: Variant 3-94049426-A-G is Benign according to our data. Variant chr3-94049426-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 346912.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00048 (73/152134) while in subpopulation NFE AF= 0.00072 (49/68020). AF 95% confidence interval is 0.00056. There are 0 homozygotes in gnomad4. There are 31 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ARL13B	NM_001174150.2	c.1045A>G	p.Lys349Glu	missense_variant	8/10	ENST00000394222.8	NP_001167621.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ARL13B	ENST00000394222.8	c.1045A>G	p.Lys349Glu	missense_variant	8/10	1	NM_001174150.2	ENSP00000377769	P1

Frequencies

GnomAD3 genomes AF: 0.000480 AC: 73 AN: 152134 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00179

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000720

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000887 AC: 220 AN: 247970 Hom.: 0 AF XY: 0.000911 AC XY: 122 AN XY: 133960

Gnomad AFR exome AF: 0.000124

Gnomad AMR exome AF: 0.0000294

Gnomad ASJ exome AF: 0.000101

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00259

Gnomad NFE exome AF: 0.00134

Gnomad OTH exome AF: 0.00149

GnomAD4 exome AF: 0.000692 AC: 1007 AN: 1454234 Hom.: 3 Cov.: 30 AF XY: 0.000684 AC XY: 495 AN XY: 723270

Gnomad4 AFR exome AF: 0.0000904

Gnomad4 AMR exome AF: 0.0000226

Gnomad4 ASJ exome AF: 0.000385

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00348

Gnomad4 NFE exome AF: 0.000672

Gnomad4 OTH exome AF: 0.00105

GnomAD4 genome AF: 0.000480 AC: 73 AN: 152134 Hom.: 0 Cov.: 31 AF XY: 0.000417 AC XY: 31 AN XY: 74334

Gnomad4 AFR AF: 0.0000965

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00179

Gnomad4 NFE AF: 0.000720

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000739 Hom.: 0

Bravo AF: 0.000348

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.00116 AC: 141

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

Joubert syndrome 8 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 26, 2024

- -

ARL13B-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 08, 2022

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	0.24
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.24
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.20	.;.;T;T
Eigen	Benign	0.18
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.88	D;D;.;D
M_CAP	Benign	0.036	D
MetaRNN	Benign	0.026	T;T;T;T
MetaSVM	Benign	-0.47	T
MutationAssessor	Benign	1.1	.;.;L;L
MutationTaster	Benign	0.89	D;D;D;D;D
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-1.8	N;N;N;N
REVEL	Benign	0.20
Sift	Uncertain	0.0040	D;D;D;D
Sift4G	Uncertain	0.0090	D;D;D;D
Polyphen		0.45, 0.12	.;B;B;B
Vest4		0.53
MVP		0.66
MPC		0.16
ClinPred		0.030	T
GERP RS		5.1
Varity_R		0.30
gMVP		0.26

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: rs139063474; hg19: chr3-93768270;