rs765715798

Variant names:

• chr3-97788002-G-A
• rs765715798
• NM_001278293.3:c.362G>A

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PM1 PM2 PP2 PP5_Very_Strong

The NM_001278293.3(ARL6):​c.362G>A​(p.Arg121His) variant causes a missense change. The variant allele was found at a frequency of 0.0000161 in 1,613,060 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R121C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: ARL6 NM_001278293.3 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:5 U:1
• Conservation: PhyloP100: 4.21

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]

ACMG classification

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

• PM1: In a chain ADP-ribosylation factor-like protein 6 (size 184) in uniprot entity ARL6_HUMAN there are 24 pathogenic changes around while only 3 benign (89%) in NM_001278293.3
• PM2: Very rare variant in population databases, with high coverage
• 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, Bardet-Biedl syndrome 3, retinitis pigmentosa 55, retinitis pigmentosa.
• PP5: Variant 3-97788002-G-A is Pathogenic according to our data. Variant chr3-97788002-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 191178.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-97788002-G-A is described in Lovd as [Likely_pathogenic]. Variant chr3-97788002-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARL6	NM_001278293.3	c.362G>A	p.Arg121His	missense_variant	Exon 6 of 8	ENST00000463745.6	NP_001265222.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARL6	ENST00000463745.6	c.362G>A	p.Arg121His	missense_variant	Exon 6 of 8	2	NM_001278293.3	ENSP00000419619.1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152128 Hom.: 0 Cov.: 32

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: 0.0000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000359 AC: 9 AN: 250632 AF XY: 0.0000221

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: 0.0000707

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000164 AC: 24 AN: 1460932 Hom.: 0 Cov.: 31 AF XY: 0.0000165 AC XY: 12 AN XY: 726790

Gnomad4 AFR exome AF: 0.0000299 AC: 1 AN: 33448

Gnomad4 AMR exome AF: 0.00 AC: 0 AN: 44656

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 26110

Gnomad4 EAS exome AF: 0.0000253 AC: 1 AN: 39592

Gnomad4 SAS exome AF: 0.0000116 AC: 1 AN: 86230

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 53364

Gnomad4 NFE exome AF: 0.0000135 AC: 15 AN: 1111426

Gnomad4 Remaining exome AF: 0.0000828 AC: 5 AN: 60354

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152128 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74318

Gnomad4 AFR AF: 0.00 AC: 0 AN: 0

Gnomad4 AMR AF: 0.00 AC: 0 AN: 0

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.00 AC: 0 AN: 0

Gnomad4 FIN AF: 0.0000943 AC: 0.0000942863 AN: 0.0000942863

Gnomad4 NFE AF: 0.0000147 AC: 0.0000147063 AN: 0.0000147063

Gnomad4 OTH AF: 0.00 AC: 0 AN: 0

Alfa AF: 0.0000199 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.0000659 AC: 8

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:5 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:1 Uncertain:1

Sep 20, 2022

GeneDx

Significance: Uncertain significance

Review Status: flagged submission

Collection Method: clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26355662, 27124789, 33090715, 28130426, 28005406) -

-

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

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

Nov 13, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 121 of the ARL6 protein (p.Arg121His). This variant is present in population databases (rs765715798, gnomAD 0.007%). This missense change has been observed in individuals with clinical features of ARL6-related conditions (PMID: 26355662, 28130426, 35457050; Invitae). ClinVar contains an entry for this variant (Variation ID: 191178). 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. This variant disrupts the p.Arg121 amino acid residue in ARL6. Other variant(s) that disrupt this residue have been observed in individuals with ARL6-related conditions (PMID: 33090715), which suggests that this may be a clinically significant amino acid residue. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Autosomal recessive retinitis pigmentosa Pathogenic:1

Sep 10, 2015

Faculty of Health Sciences, Beirut Arab University

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

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

Jun 11, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Bardet-Biedl syndrome Pathogenic:1

Nov 21, 2022

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: ARL6 c.362G>A (p.Arg121His) results in a non-conservative amino acid change located in the small GTP-binding protein domain (IPR005225) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.6e-05 in 250632 control chromosomes (gnomAD). The variant, c.362G>A, has been reported in the literature in at least three homozygous individuals affected with retinal dystrophy (Patel_2016, Abouelhoda_2016, Biswas_2017, Ramkumar_2017, Gonzalez-Iglesias_2022). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. A different missense change affecting the same amino acid (c.361C>T (p.R121C)) is reported in individual(s) affected with retinal dystrophy (HGMD), suggesting a functional role for this residue. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and classified the variant as pathogenic (n=1) and uncertain significance (n=1). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.0044	T
BayesDel_noAF	Uncertain	-0.060
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.65	D;D;D;T;.
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.99	.;D;.;D;D
M_CAP	Uncertain	0.11	D
MetaRNN	Uncertain	0.63	D;D;D;D;D
MetaSVM	Benign	-0.33	T
MutationAssessor	Uncertain	2.7	M;M;M;.;.
PrimateAI	Pathogenic	0.84	D
PROVEAN	Uncertain	-3.8	D;D;D;D;.
REVEL	Uncertain	0.55
Sift	Uncertain	0.0060	D;D;D;D;.
Sift4G	Uncertain	0.0050	D;D;D;D;D
Polyphen		1.0	D;D;D;.;.
Vest4		0.79
MutPred		0.51		Gain of disorder (P = 0.1155);Gain of disorder (P = 0.1155);Gain of disorder (P = 0.1155);Gain of disorder (P = 0.1155);.;
MVP		0.86
MPC		0.50
ClinPred		0.89	D
GERP RS		5.5
Varity_R		0.44
gMVP		0.61
Mutation Taster		=8/92	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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

Other links and lift over

dbSNP: rs765715798; hg19: chr3-97506846; COSMIC: COSV60118779;