2-151814213-C-G

Variant names:

• chr2-151814213-C-G
• rs1338396146
• NM_012097.4:c.211G>C

Variant summary

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

The NM_012097.4(ARL5A):​c.211G>C​(p.Glu71Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000275 in 1,454,880 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: ARL5A NM_012097.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.86

Genes affected

ARL5A (HGNC:696): (ADP ribosylation factor like GTPase 5A) The protein encoded by this gene belongs to the ARF family of GTP-binding proteins. With its distinctive nuclear/nucleolar localization and interaction with HP1alpha, the protein is developmentally regulated and may play a role(s) in nuclear dynamics and/or signaling cascades during embryonic development. Alternative splicing results in multiple transcript variants encoding different isoforms. This gene has multiple pseudogenes. [provided by RefSeq, Jul 2008]

ENSG00000283228 (HGNC:):

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
ARL5A	NM_012097.4	c.211G>C	p.Glu71Gln	missense_variant	Exon 3 of 6	ENST00000295087.13	NP_036229.1
ARL5A	NM_001037174.2	c.100G>C	p.Glu34Gln	missense_variant	Exon 3 of 6		NP_001032251.1
ARL5A	NM_177985.3	c.100G>C	p.Glu34Gln	missense_variant	Exon 3 of 6		NP_817114.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARL5A	ENST00000295087.13	c.211G>C	p.Glu71Gln	missense_variant	Exon 3 of 6	1	NM_012097.4	ENSP00000295087.8
ENSG00000283228	ENST00000637559.1	n.*497G>C		downstream_gene_variant		5		ENSP00000489697.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000122 AC: 3 AN: 245690 Hom.: 0 AF XY: 0.00000752 AC XY: 1 AN XY: 133050

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000905

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000275 AC: 4 AN: 1454880 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 723820

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000685

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000255

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 01, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.211G>C (p.E71Q) alteration is located in exon 3 (coding exon 3) of the ARL5A gene. This alteration results from a G to C substitution at nucleotide position 211, causing the glutamic acid (E) at amino acid position 71 to be replaced by a glutamine (Q). 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	Uncertain	0.35
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Pathogenic	0.25
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.072	T;.
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D;D
M_CAP	Uncertain	0.093	D
MetaRNN	Uncertain	0.69	D;D
MetaSVM	Uncertain	-0.024	T
MutationAssessor	Benign	1.1	L;.
PrimateAI	Pathogenic	0.79	T
PROVEAN	Benign	-1.7	N;N
REVEL	Pathogenic	0.68
Sift	Benign	0.18	T;T
Sift4G	Benign	0.17	T;T
Polyphen		0.59	P;.
Vest4		0.86
MutPred		0.44		Gain of MoRF binding (P = 0.0575);.;
MVP		0.83
MPC		0.34
ClinPred		0.55	D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.53
gMVP		0.49

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1338396146; hg19: chr2-152670727;