rs104893679

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1PM2PP3_StrongPP5_Moderate

The NM_001278293.3(ARL6):c.506G>C(p.Gly169Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000118 in 1,613,646 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G169C) has been classified as Uncertain significance.

Frequency

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

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

ARL6
NM_001278293.3 missense

Scores

Clinical Significance

Pathogenic criteria provided, single submitter P:2O:1

Conservation

PhyloP100: 9.52

Variant links:

Genes affected

ARL6 (HGNC:13210): (ADP ribosylation factor like GTPase 6) The protein encoded by this gene belongs to the ARF-like (ADP ribosylation factor-like) sub-family of the ARF family of GTP-binding proteins which are involved in regulation of intracellular traffic. Mutations in this gene are associated with Bardet-Biedl syndrome (BBS). A vision-specific transcript, encoding long isoform BBS3L, has been described (PMID: 20333246). [provided by RefSeq, Apr 2016]

ARL6 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 7 uncertain in NM_001278293.3

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.988

PP5

Variant 3-97791797-G-C is Pathogenic according to our data. Variant chr3-97791797-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 2041.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ARL6	NM_001278293.3 linkuse as main transcript	c.506G>C	p.Gly169Ala	missense_variant	7/8	ENST00000463745.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ARL6	ENST00000463745.6 linkuse as main transcript	c.506G>C	p.Gly169Ala	missense_variant	7/8	2	NM_001278293.3	P1	Q9H0F7-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152182

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251336

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135834

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000880

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000123

AC:

AN:

1461464

Hom.:

Cov.:

AF XY:

0.00000963

AC XY:

AN XY:

727058

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:

0.0000153

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152182

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74340

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2Other:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Bardet-Biedl syndrome 3;C3150808:Retinitis pigmentosa 55

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Oct 06, 2023

This sequence change replaces glycine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 169 of the ARL6 protein (p.Gly169Ala). This variant is present in population databases (rs104893679, gnomAD 0.0009%). This missense change has been observed in individual(s) with Bardet-Biedl syndrome (PMID: 15314642). It has also been observed to segregate with disease in related individuals. This variant is also known as 859G>C G169A. ClinVar contains an entry for this variant (Variation ID: 2041). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects ARL6 function (PMID: 19236846). For these reasons, this variant has been classified as Pathogenic. -

Bardet-Biedl syndrome 3

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Sep 01, 2004

- -

Bardet-Biedl syndrome 1, modifier of

Other:1

risk factor, no assertion criteria provided

literature only

OMIM

Sep 01, 2004

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.85

BayesDel_addAF

Pathogenic

0.45

BayesDel_noAF

Pathogenic

0.41

Cadd

Pathogenic

Dann

Uncertain

1.0

DEOGEN2

Pathogenic

0.80

D;D;D;.

Eigen

Pathogenic

0.94

Eigen_PC

Pathogenic

0.83

FATHMM_MKL

Pathogenic

0.99

M_CAP

Pathogenic

0.41

MetaRNN

Pathogenic

0.99

D;D;D;D

MetaSVM

Pathogenic

0.94

MutationAssessor

Pathogenic

3.8

H;H;H;.

MutationTaster

Benign

1.0

A;A;A

PrimateAI

Pathogenic

0.79

PROVEAN

Pathogenic

-5.6

D;D;D;.

REVEL

Pathogenic

0.95

Sift

Pathogenic

0.0

D;D;D;.

Sift4G

Uncertain

0.0030

D;D;D;D

Polyphen

1.0

D;D;D;.

Vest4

0.98

MutPred

0.95

Loss of glycosylation at K166 (P = 0.0486);Loss of glycosylation at K166 (P = 0.0486);Loss of glycosylation at K166 (P = 0.0486);.;

MVP

0.96

MPC

0.61

ClinPred

1.0

GERP RS

4.4

Varity_R

0.96

gMVP

0.83

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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