Genetic Variant ARL9:p.Leu260Val (chr4-56523856-C-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001363794.2(ARL9):c.778C>G(p.Leu260Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000124 in 1,613,592 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 10/16 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

ARL9
NM_001363794.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.751

Variant links:

Genes affected

ARL9 (HGNC:23592): (ADP ribosylation factor like GTPase 9) ARL9 is a member of the small GTPase protein family with a high degree of similarity to ARF (MIM 103180) proteins of the RAS superfamily.[supplied by OMIM, Nov 2008]

ARL9 links:

LOC105377665 (HGNC:):

LOC105377665 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.22077858).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARL9	NM_001363794.2 link	c.778C>G	p.Leu260Val	missense_variant	Exon 4 of 4	ENST00000640821.3	NP_001350723.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ARL9	ENST00000640821.3 link	c.778C>G	p.Leu260Val	missense_variant	Exon 4 of 4	5	NM_001363794.2	ENSP00000492671.3	A0A1W2PS79
ARL9	ENST00000360096.3 link	c.352C>G	p.Leu118Val	missense_variant	Exon 4 of 4	1		ENSP00000353210.2	Q6T311-2
ARL9	ENST00000645327.1 link	n.*273C>G		non_coding_transcript_exon_variant	Exon 3 of 3			ENSP00000496178.1	A0A2R8YGM7
ARL9	ENST00000645327.1 link	n.*273C>G		3_prime_UTR_variant	Exon 3 of 3			ENSP00000496178.1	A0A2R8YGM7

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152236

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461356

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726970

show subpopulations

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:

9.00e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152236

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74364

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000312

Hom.:

Bravo

AF:

0.0000189

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Oct 06, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.352C>G (p.L118V) alteration is located in exon 4 (coding exon 3) of the ARL9 gene. This alteration results from a C to G substitution at nucleotide position 352, causing the leucine (L) at amino acid position 118 to be replaced by a valine (V). 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

BayesDel_addAF

Benign

-0.096

BayesDel_noAF

Benign

-0.38

CADD

Benign

DANN

Uncertain

1.0

Eigen

Benign

0.045

Eigen_PC

Benign

-0.021

FATHMM_MKL

Uncertain

0.79

LIST_S2

Benign

0.68

T;T

M_CAP

Benign

0.022

MetaRNN

Benign

0.22

T;T

MetaSVM

Benign

-0.59

PrimateAI

Benign

0.46

REVEL

Uncertain

0.30

Sift4G

Uncertain

0.0080

D;.

Vest4

0.36

MVP

0.46

MPC

0.44

ClinPred

0.92

GERP RS

1.5

gMVP

0.57

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over