chr3-94049453-C-G

Variant names:

• chr3-94049453-C-G
• NM_001174150.2:c.1072C>G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001174150.2(ARL13B):​c.1072C>G​(p.Arg358Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R358Q) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: ARL13B NM_001174150.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.941

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARL13B	NM_001174150.2	c.1072C>G	p.Arg358Gly	missense_variant	Exon 8 of 10	ENST00000394222.8	NP_001167621.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARL13B	ENST00000394222.8	c.1072C>G	p.Arg358Gly	missense_variant	Exon 8 of 10	1	NM_001174150.2	ENSP00000377769.3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Jul 31, 2023

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.38
BayesDel_addAF	Benign	-0.020	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.22	.;.;T;T
Eigen	Benign	0.17
Eigen_PC	Benign	0.19
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Uncertain	0.92	D;D;.;D
M_CAP	Benign	0.059	D
MetaRNN	Uncertain	0.58	D;D;D;D
MetaSVM	Benign	-0.32	T
MutationAssessor	Benign	1.2	.;.;L;L
PrimateAI	Uncertain	0.50	T
PROVEAN	Uncertain	-2.5	D;N;N;N
REVEL	Benign	0.090
Sift	Uncertain	0.0030	D;D;D;D
Sift4G	Uncertain	0.0070	D;D;D;D
Polyphen		0.68, 0.30	.;P;B;B
Vest4		0.65
MutPred		0.40		.;.;Gain of sheet (P = 0.0085);Gain of sheet (P = 0.0085);
MVP		0.76
MPC		0.26
ClinPred		0.92	D
GERP RS		3.2
Varity_R		0.20
gMVP		0.44

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr3-93768297;