rs201736026

Variant names:

• chr3-97768156-G-A
• rs201736026
• NM_001278293.3:c.49G>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PP2

The NM_001278293.3(ARL6):​c.49G>A​(p.Glu17Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000356 in 1,460,876 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E17D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000036 (0 hom.)
• Consequence: ARL6 NM_001278293.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 9.35
• Publications: 0 publications found

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: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics, Genomics England PanelApp
• ciliopathy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• retinitis pigmentosa 55

  Inheritance: AR Classification: STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• retinitis pigmentosa

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Bardet-Biedl syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001278293.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARL6	NM_001278293.3	MANE Select	c.49G>A	p.Glu17Lys	missense	Exon 2 of 8	NP_001265222.1	Q9H0F7-1
	ARL6	NM_001323513.2		c.49G>A	p.Glu17Lys	missense	Exon 2 of 9	NP_001310442.1	Q9H0F7-2
	ARL6	NM_032146.5		c.49G>A	p.Glu17Lys	missense	Exon 3 of 9	NP_115522.1	Q9H0F7-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARL6	ENST00000463745.6	TSL:2 MANE Select	c.49G>A	p.Glu17Lys	missense	Exon 2 of 8	ENSP00000419619.1	Q9H0F7-1
	ARL6	ENST00000493990.5	TSL:1	n.49G>A		non_coding_transcript_exon	Exon 3 of 10	ENSP00000418057.1	Q9H0F7-1
	ARL6	ENST00000496713.1	TSL:1	n.287G>A		non_coding_transcript_exon	Exon 2 of 7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251330 AF XY: 0.00000736

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000356 AC: 52 AN: 1460876 Hom.: 0 Cov.: 31 AF XY: 0.0000399 AC XY: 29 AN XY: 726736

African (AFR) AF: 0.00 AC: 0 AN: 33458

American (AMR) AF: 0.00 AC: 0 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26108

East Asian (EAS) AF: 0.00 AC: 0 AN: 39640

South Asian (SAS) AF: 0.00 AC: 0 AN: 86228

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53408

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.0000423 AC: 47 AN: 1111206

Other (OTH) AF: 0.0000829 AC: 5 AN: 60348

GnomAD4 genome Cov.: 32

Alfa AF: 0.000113 Hom.: 0

Bravo AF: 0.0000264

EpiCase AF: 0.000164

EpiControl AF: 0.00

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	ARL6-related disorder (1)
-	1	-	Bardet-Biedl syndrome 3;C2936862:Bardet-Biedl syndrome 1;C3150808:Retinitis pigmentosa 55 (1)
-	1	-	Bardet-Biedl syndrome 3;C3150808:Retinitis pigmentosa 55 (1)
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.35
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.030
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.25	T
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.043	D
MetaRNN	Uncertain	0.60	D
MetaSVM	Uncertain	-0.0049	T
MutationAssessor	Benign	1.5	L
PhyloP100		9.4
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-1.7	N
REVEL	Uncertain	0.44
Sift	Benign	0.57	T
Sift4G	Benign	0.33	T
Polyphen		1.0	D
Vest4		0.75
MVP		0.86
MPC		0.15
ClinPred		0.65	D
GERP RS		5.5
Varity_R		0.69
gMVP		0.88
Mutation Taster		=56/44	polymorphism

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

Other links and lift over

dbSNP: rs201736026; hg19: chr3-97487000;