Genetic Variant NM_012097.4:c.221G>A (chr2-151814203-C-T) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_012097.4(ARL5A):c.221G>A(p.Arg74His) variant causes a missense change. The variant allele was found at a frequency of 0.0000181 in 1,605,748 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000018 ( 0 hom. )

Consequence

ARL5A
NM_012097.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.13

Publications

0 publications found

Variant links:

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]

ARL5A links:

ENSG00000283228 (HGNC:):

ENSG00000283228 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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, 0.953

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ARL5A	NM_012097.4	MANE Select	c.221G>A	p.Arg74His	missense	Exon 3 of 6	NP_036229.1	Q9Y689-1
ARL5A	NM_001037174.2		c.110G>A	p.Arg37His	missense	Exon 3 of 6	NP_001032251.1	Q9Y689-2
ARL5A	NM_177985.3		c.110G>A	p.Arg37His	missense	Exon 3 of 6	NP_817114.2	Q9Y689-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ARL5A	ENST00000295087.13	TSL:1 MANE Select	c.221G>A	p.Arg74His	missense	Exon 3 of 6	ENSP00000295087.8	Q9Y689-1
ARL5A	ENST00000899624.1		c.254G>A	p.Arg85His	missense	Exon 4 of 6	ENSP00000569683.1
ARL5A	ENST00000899623.1		c.221G>A	p.Arg74His	missense	Exon 3 of 5	ENSP00000569682.1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152144

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000122

AC:

AN:

245054

AF XY:

0.0000151

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000179

Gnomad OTH exome

AF:

0.000169

GnomAD4 exome

AF:

0.0000179

AC:

AN:

1453604

Hom.:

Cov.:

AF XY:

0.0000152

AC XY:

AN XY:

723110

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32920

American (AMR)

AF:

0.00

AC:

AN:

43514

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25898

East Asian (EAS)

AF:

0.00

AC:

AN:

39236

South Asian (SAS)

AF:

0.00

AC:

AN:

84814

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53314

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4414

European-Non Finnish (NFE)

AF:

0.0000225

AC:

AN:

1109540

Other (OTH)

AF:

0.0000167

AC:

AN:

59954

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152144

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74322

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41434

American (AMR)

AF:

0.00

AC:

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5200

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10584

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000441

AC:

AN:

68018

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.458

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000282

Hom.:

Bravo

AF:

0.0000189

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000120

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.96

BayesDel_addAF

Pathogenic

0.39

BayesDel_noAF

Pathogenic

0.38

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.33

Eigen

Pathogenic

0.97

Eigen_PC

Pathogenic

0.87

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.90

M_CAP

Pathogenic

0.29

MetaRNN

Pathogenic

0.95

MetaSVM

Pathogenic

0.83

MutationAssessor

Pathogenic

4.3

PhyloP100

6.1

PrimateAI

Pathogenic

0.82

PROVEAN

Uncertain

-4.2

REVEL

Pathogenic

0.84

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.71

MutPred

0.93

Gain of catalytic residue at L73 (P = 0.1048)

MVP

0.96

MPC

0.26

ClinPred

1.0

GERP RS

5.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.84

gMVP

0.77

Mutation Taster

=23/77

disease causing

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over