NM_001667.4:c.29T>C

Variant names:

• chr11-65014236-T-C
• rs938322910
• NM_001667.4:c.29T>C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001667.4(ARL2):​c.29T>C​(p.Met10Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000141 in 1,422,168 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ARL2 NM_001667.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.29

Genes affected

ARL2 (HGNC:693): (ADP ribosylation factor like GTPase 2) This gene encodes a small GTP-binding protein of the RAS superfamily which functions as an ADP-ribosylation factor (ARF). The encoded protein is one of a functionally distinct group of ARF-like genes. [provided by RefSeq, Jul 2008]

ARL2-SNX15 (HGNC:49197): (ARL2-SNX15 readthrough (NMD candidate)) This locus represents naturally occurring read-through transcription between the neighboring ADP-ribosylation factor-like 2 (ARL2) and sorting nexin 15 (SNX15) genes on chromosome 11. The read-through transcript is a candidate for nonsense-mediated mRNA decay (NMD), and is therefore unlikely to produce a protein product. [provided by RefSeq, Dec 2010]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2927407).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARL2	NM_001667.4	c.29T>C	p.Met10Thr	missense_variant	Exon 1 of 5	ENST00000246747.9	NP_001658.2
ARL2	NM_001199745.2	c.29T>C	p.Met10Thr	missense_variant	Exon 1 of 4		NP_001186674.1
ARL2-SNX15	NR_037650.2	n.77T>C		non_coding_transcript_exon_variant	Exon 1 of 11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARL2	ENST00000246747.9	c.29T>C	p.Met10Thr	missense_variant	Exon 1 of 5	1	NM_001667.4	ENSP00000246747.4
ARL2-SNX15	ENST00000301886.3	n.29T>C		non_coding_transcript_exon_variant	Exon 1 of 11	2		ENSP00000476630.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000141 AC: 2 AN: 1422168 Hom.: 0 Cov.: 30 AF XY: 0.00000283 AC XY: 2 AN XY: 707032

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000182

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000370 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 15, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.29T>C (p.M10T) alteration is located in exon 1 (coding exon 1) of the ARL2 gene. This alteration results from a T to C substitution at nucleotide position 29, causing the methionine (M) at amino acid position 10 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.61
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.030
CADD	Uncertain	23
DANN	Benign	0.94
DEOGEN2	Benign	0.045	T;T;.
Eigen	Benign	-0.15
Eigen_PC	Benign	0.053
FATHMM_MKL	Benign	0.73	D
LIST_S2	Uncertain	0.90	.;D;D
M_CAP	Benign	0.046	D
MetaRNN	Benign	0.29	T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	-0.17	N;N;N
PrimateAI	Pathogenic	0.91	D
PROVEAN	Benign	-1.3	N;N;N
REVEL	Benign	0.27
Sift	Benign	0.27	T;T;T
Sift4G	Benign	0.20	T;T;T
Polyphen		0.0020	B;B;.
Vest4		0.58
MVP		0.59
MPC		0.32
ClinPred		0.90	D
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.82
gMVP		0.71

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: rs938322910; hg19: chr11-64781708;