3-94050868-C-G

Variant names:

• chr3-94050868-C-G
• rs11554412
• NM_001174150.2:c.1186C>G

Variant summary

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

The NM_001174150.2(ARL13B):​c.1186C>G​(p.Pro396Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00716 in 1,612,916 control chromosomes in the GnomAD database, including 50 homozygotes. 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 Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. P396P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0052 (8 hom., cov: 32)
  • Exomes 𝑓: 0.0074 (42 hom.)
• Consequence: ARL13B NM_001174150.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 2.16
• Publications: 12 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]

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

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.008797377).
• BP6: Variant 3-94050868-C-G is Benign according to our data. Variant chr3-94050868-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 199197.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 = 0.0052 (792/152194) while in subpopulation NFE AF = 0.00822 (559/67994). AF 95% confidence interval is 0.00766. There are 8 homozygotes in GnomAd4. There are 364 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 8 AR gene

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARL13B	NM_001174150.2	MANE Select	c.1186C>G	p.Pro396Ala	missense	Exon 9 of 10	NP_001167621.1	Q3SXY8-1
	ARL13B	NM_182896.3		c.1186C>G	p.Pro396Ala	missense	Exon 9 of 11	NP_878899.1	Q3SXY8-1
	ARL13B	NM_001321328.2		c.1141C>G	p.Pro381Ala	missense	Exon 10 of 11	NP_001308257.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARL13B	ENST00000394222.8	TSL:1 MANE Select	c.1186C>G	p.Pro396Ala	missense	Exon 9 of 10	ENSP00000377769.3	Q3SXY8-1
	ARL13B	ENST00000471138.5	TSL:1	c.1186C>G	p.Pro396Ala	missense	Exon 9 of 11	ENSP00000420780.1	Q3SXY8-1
	ARL13B	ENST00000535334.5	TSL:1	c.877C>G	p.Pro293Ala	missense	Exon 8 of 9	ENSP00000445145.1	Q3SXY8-3

Frequencies

GnomAD3 genomes AF: 0.00522 AC: 794 AN: 152076 Hom.: 8 Cov.: 32

Gnomad AFR AF: 0.00133

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00583

Gnomad ASJ AF: 0.00490

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00373

Gnomad FIN AF: 0.00359

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00822

Gnomad OTH AF: 0.00767

GnomAD2 exomes AF: 0.00605 AC: 1518 AN: 250934 AF XY: 0.00616

Gnomad AFR exome AF: 0.00117

Gnomad AMR exome AF: 0.00500

Gnomad ASJ exome AF: 0.00387

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00404

Gnomad NFE exome AF: 0.00917

Gnomad OTH exome AF: 0.00719

GnomAD4 exome AF: 0.00737 AC: 10764 AN: 1460722 Hom.: 42 Cov.: 30 AF XY: 0.00726 AC XY: 5276 AN XY: 726684

African (AFR) AF: 0.00129 AC: 43 AN: 33452

American (AMR) AF: 0.00497 AC: 222 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.00452 AC: 118 AN: 26118

East Asian (EAS) AF: 0.00 AC: 0 AN: 39608

South Asian (SAS) AF: 0.00399 AC: 344 AN: 86242

European-Finnish (FIN) AF: 0.00513 AC: 271 AN: 52850

Middle Eastern (MID) AF: 0.00555 AC: 32 AN: 5762

European-Non Finnish (NFE) AF: 0.00840 AC: 9343 AN: 1111618

Other (OTH) AF: 0.00648 AC: 391 AN: 60366

GnomAD4 genome AF: 0.00520 AC: 792 AN: 152194 Hom.: 8 Cov.: 32 AF XY: 0.00489 AC XY: 364 AN XY: 74416

African (AFR) AF: 0.00132 AC: 55 AN: 41536

American (AMR) AF: 0.00582 AC: 89 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00490 AC: 17 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00353 AC: 17 AN: 4820

European-Finnish (FIN) AF: 0.00359 AC: 38 AN: 10588

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00822 AC: 559 AN: 67994

Other (OTH) AF: 0.00759 AC: 16 AN: 2108

Alfa AF: 0.00693 Hom.: 0

Bravo AF: 0.00519

TwinsUK AF: 0.0121 AC: 45

ALSPAC AF: 0.00752 AC: 29

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00814 AC: 70

ExAC AF: 0.00647 AC: 785

Asia WGS AF: 0.00231 AC: 8 AN: 3476

EpiCase AF: 0.00714

EpiControl AF: 0.00842

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	4	not specified (4)
-	-	1	Joubert syndrome 1 (1)
-	-	1	Joubert syndrome 8 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.46	T
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.79	T
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.0088	T
MetaSVM	Uncertain	-0.10	T
MutationAssessor	Benign	1.7	L
PhyloP100		2.2
PrimateAI	Benign	0.42	T
PROVEAN	Uncertain	-2.5	D
REVEL	Benign	0.20
Sift	Uncertain	0.010	D
Sift4G	Benign	0.24	T
Polyphen		1.0	D
Vest4		0.40
MVP		0.83
MPC		0.077
ClinPred		0.030	T
GERP RS		5.5
Varity_R		0.065
gMVP		0.27
Mutation Taster		=95/5	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: rs11554412; hg19: chr3-93769712;