NM_001278293.3:c.281T>C

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PM1PP2PP3_ModeratePP5_Very_Strong

The NM_001278293.3(ARL6):c.281T>C(p.Ile94Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000018 in 1,612,688 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

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

Exomes 𝑓: 0.000018 ( 0 hom. )

Consequence

ARL6
NM_001278293.3 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 7.54

Publications

4 publications found

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 Gene-Disease associations (from GenCC):

Bardet-Biedl syndrome 3
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Genomics England PanelApp, G2P
retinitis pigmentosa 55
Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
retinitis pigmentosa
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Bardet-Biedl syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ARL6 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 13 ACMG points.

PM1

In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_001278293.3

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 10 curated pathogenic missense variants (we use a threshold of 10). The gene has 2 curated benign missense variants. Gene score misZ: 0.55514 (below the threshold of 3.09). Trascript score misZ: 0.75863 (below the threshold of 3.09). GenCC associations: The gene is linked to Bardet-Biedl syndrome 3, retinitis pigmentosa 55, retinitis pigmentosa, Bardet-Biedl syndrome.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.911

PP5

Variant 3-97784981-T-C is Pathogenic according to our data. Variant chr3-97784981-T-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 438186.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARL6	NM_001278293.3 link	c.281T>C	p.Ile94Thr	missense_variant	Exon 5 of 8	ENST00000463745.6	NP_001265222.1	Q9H0F7-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARL6	ENST00000463745.6 link	c.281T>C	p.Ile94Thr	missense_variant	Exon 5 of 8	2	NM_001278293.3	ENSP00000419619.1		Q9H0F7-1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152054

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.0000295

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000319

AC:

AN:

251138

AF XY:

0.0000295

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000264

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000178

AC:

AN:

1460634

Hom.:

Cov.:

AF XY:

0.0000248

AC XY:

AN XY:

726686

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33444

American (AMR)

AF:

0.00

AC:

AN:

44692

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26088

East Asian (EAS)

AF:

0.0000253

AC:

AN:

39522

South Asian (SAS)

AF:

0.000116

AC:

AN:

86226

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53386

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.0000135

AC:

AN:

1111174

Other (OTH)

AF:

0.00

AC:

AN:

60342

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.454

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:

152054

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74262

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41466

American (AMR)

AF:

0.00

AC:

AN:

15268

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5200

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000295

AC:

AN:

67896

Other (OTH)

AF:

0.00

AC:

AN:

2082

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.0000330

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3470

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Bardet-Biedl syndrome 3;C3150808:Retinitis pigmentosa 55

Pathogenic:1

Feb 18, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 94 of the ARL6 protein (p.Ile94Thr). This variant is present in population databases (rs771054395, gnomAD 0.01%). This missense change has been observed in individuals with ARL6-related conditions (PMID: 23219996, 28041643, 33946315). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 438186). 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. For these reasons, this variant has been classified as Pathogenic. -

Bardet-Biedl syndrome 3;C2936862:Bardet-Biedl syndrome 1;C3150808:Retinitis pigmentosa 55

Pathogenic:1

Jun 15, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

ARL6-related disorder

Pathogenic:1

Aug 12, 2024

PreventionGenetics, part of Exact Sciences

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

The ARL6 c.281T>C variant is predicted to result in the amino acid substitution p.Ile94Thr. This variant has been reported in the homozygous state in a patient with Bardet-Biedl syndrome (see, for example, Khan et al. 2013. PubMed ID: 23219996). This variant is reported in 0.013% of alleles in individuals of South Asian descent in gnomAD. This variant is interpreted as likely pathogenic. -

Retinitis pigmentosa

Pathogenic:1

Jan 01, 2015

NIHR Bioresource Rare Diseases, University of Cambridge

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:research

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.51

BayesDel_addAF

Pathogenic

0.19

BayesDel_noAF

Pathogenic

0.27

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.75

D;D;D;T;.

Eigen

Pathogenic

0.91

Eigen_PC

Pathogenic

0.82

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.93

.;D;.;D;D

M_CAP

Uncertain

0.27

MetaRNN

Pathogenic

0.91

D;D;D;D;D

MetaSVM

Uncertain

0.50

MutationAssessor

Pathogenic

3.1

M;M;M;.;.

PhyloP100

7.5

PrimateAI

Uncertain

0.67

PROVEAN

Uncertain

-4.0

D;D;D;D;.

REVEL

Pathogenic

0.88

Sift

Uncertain

0.0010

D;D;D;D;.

Sift4G

Uncertain

0.0040

D;D;D;D;D

Polyphen

0.97

D;D;D;.;.

Vest4

0.96

MutPred

0.75

Loss of sheet (P = 0.0104);Loss of sheet (P = 0.0104);Loss of sheet (P = 0.0104);Loss of sheet (P = 0.0104);.;

MVP

0.93

MPC

0.67

ClinPred

0.88

GERP RS

5.3

PromoterAI

0.0058

Neutral

(source)

Varity_R

0.94

gMVP

0.80

Mutation Taster

=2/98

disease causing (ClinVar)

(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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over