2-151814203-C-A

Variant names:

• chr2-151814203-C-A
• rs747897247
• NM_012097.4:c.221G>T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_012097.4(ARL5A):​c.221G>T​(p.Arg74Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R74H) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ARL5A NM_012097.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.13
• Publications: 0 publications found

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

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.975

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_012097.4. 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
	ARL5A	NM_012097.4	MANE Select	c.221G>T	p.Arg74Leu	missense	Exon 3 of 6	NP_036229.1	Q9Y689-1
	ARL5A	NM_001037174.2		c.110G>T	p.Arg37Leu	missense	Exon 3 of 6	NP_001032251.1	Q9Y689-2
	ARL5A	NM_177985.3		c.110G>T	p.Arg37Leu	missense	Exon 3 of 6	NP_817114.2	Q9Y689-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARL5A	ENST00000295087.13	TSL:1 MANE Select	c.221G>T	p.Arg74Leu	missense	Exon 3 of 6	ENSP00000295087.8	Q9Y689-1
	ARL5A	ENST00000899624.1		c.254G>T	p.Arg85Leu	missense	Exon 4 of 6	ENSP00000569683.1
	ARL5A	ENST00000899623.1		c.221G>T	p.Arg74Leu	missense	Exon 3 of 5	ENSP00000569682.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.34
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.34	T
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.84	T
M_CAP	Uncertain	0.27	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Uncertain	0.31	D
MutationAssessor	Pathogenic	4.3	H
PhyloP100		6.1
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-6.3	D
REVEL	Pathogenic	0.82
Sift	Uncertain	0.016	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.18	B
Vest4		0.96
MutPred		0.89		Loss of catalytic residue at R74 (P = 0.0436)
MVP		0.85
MPC		0.22
ClinPred		1.0	D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.89
gMVP		0.83
Mutation Taster		=23/77	disease causing

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

Other links and lift over

dbSNP: rs747897247; hg19: chr2-152670717;