Genetic Variant ARL6:p.Thr31Met (chr3-97768199-C-T) – ACMG Classification: Pathogenic (16 pts)

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong

The NM_001278293.3(ARL6):c.92C>T(p.Thr31Met) variant causes a missense change. The variant allele was found at a frequency of 0.00000411 in 1,460,658 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 Pathogenic (★★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

ARL6
NM_001278293.3 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:5

Conservation

PhyloP100: 5.63

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:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PM1

In a binding_site (size 0) in uniprot entity ARL6_HUMAN

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.988

PP5

Variant 3-97768199-C-T is Pathogenic according to our data. Variant chr3-97768199-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 2042.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-97768199-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARL6	NM_001278293.3 link	c.92C>T	p.Thr31Met	missense_variant	Exon 2 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.92C>T	p.Thr31Met	missense_variant	Exon 2 of 8	2	NM_001278293.3	ENSP00000419619.1		Q9H0F7-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251132

Hom.:

AF XY:

0.00000737

AC XY:

AN XY:

135726

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000411

AC:

AN:

1460658

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

726614

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000270

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Bardet-Biedl syndrome 3;C3150808:Retinitis pigmentosa 55

Pathogenic:1

Jan 21, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 31 of the ARL6 protein (p.Thr31Met). This variant is present in population databases (rs104893680, gnomAD 0.006%). This missense change has been observed in individual(s) with Bardet Biedl syndrome (PMID: 15314642, 22410627). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 2042). 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). This variant disrupts the p.Thr31 amino acid residue in ARL6. Other variant(s) that disrupt this residue have been determined to be pathogenic (internal data). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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

Feb 18, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Pathogenic:1

Dec 16, 2021

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Bardet-Biedl syndrome 3

Pathogenic:1

Sep 01, 2004

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Retinitis pigmentosa

Pathogenic:1

Apr 01, 2021

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

The p.Thr31Met variant in ARL6 was identified in an individual with Retinitis pigmentosa, via a collaborative study between the Broad Institute's Center for Mendelian Genomics and the Pierce lab (https://oculargenomics.meei.harvard.edu/labs/pierce-lab/lab-members/). Through a review of available evidence we were able to apply the following criteria: PM2, PP3, PM1, PS3, PP1, PM3-P. Based on this evidence we have classified this variant as Pathogenic. If you have any questions about the classification please reach out to the Pierce Lab. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.97

BayesDel_addAF

Pathogenic

0.33

BayesDel_noAF

Pathogenic

0.41

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.89

D;D;D;D

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.89

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.96

.;D;.;D

M_CAP

Pathogenic

0.41

MetaRNN

Pathogenic

0.99

D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

4.7

H;H;H;.

PrimateAI

Pathogenic

0.84

PROVEAN

Uncertain

-4.3

D;D;D;D

REVEL

Pathogenic

0.90

Sift

Uncertain

0.0010

D;D;D;D

Sift4G

Pathogenic

0.0010

D;D;D;D

Polyphen

1.0

D;D;D;.

Vest4

0.97

MutPred

0.96

Loss of methylation at K30 (P = 0.0292);Loss of methylation at K30 (P = 0.0292);Loss of methylation at K30 (P = 0.0292);Loss of methylation at K30 (P = 0.0292);

MVP

0.97

MPC

0.61

ClinPred

1.0

GERP RS

5.4

Varity_R

0.87

gMVP

0.88

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