chr3-97784906-A-G

Variant names:

• chr3-97784906-A-G
• rs138194402
• NM_001278293.3:c.255-49A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001278293.3(ARL6):​c.255-49A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0122 in 1,408,448 control chromosomes in the GnomAD database, including 136 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0092 (13 hom., cov: 32)
  • Exomes 𝑓: 0.013 (123 hom.)
• Consequence: ARL6 NM_001278293.3 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0530
• 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: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P
• 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 3-97784906-A-G is Benign according to our data. Variant chr3-97784906-A-G is described in ClinVar as Likely_benign. ClinVar VariationId is 262015.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00922 (1402/152120) while in subpopulation NFE AF = 0.0152 (1032/67864). AF 95% confidence interval is 0.0144. There are 13 homozygotes in GnomAd4. There are 663 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 13 AR,AD gene

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.255-49A>G		intron	N/A	NP_001265222.1	Q9H0F7-1
	ARL6	NM_001323513.2		c.255-49A>G		intron	N/A	NP_001310442.1	Q9H0F7-2
	ARL6	NM_032146.5		c.255-49A>G		intron	N/A	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.255-49A>G		intron	N/A	ENSP00000419619.1	Q9H0F7-1
	ARL6	ENST00000493990.5	TSL:1	n.255-49A>G		intron	N/A	ENSP00000418057.1	Q9H0F7-1
	ARL6	ENST00000496713.1	TSL:1	n.493-49A>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00922 AC: 1402 AN: 152002 Hom.: 13 Cov.: 32

Gnomad AFR AF: 0.00249

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0134

Gnomad ASJ AF: 0.00490

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00208

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.0152

Gnomad OTH AF: 0.00913

GnomAD2 exomes AF: 0.00887 AC: 2011 AN: 226724 AF XY: 0.00871

Gnomad AFR exome AF: 0.00320

Gnomad AMR exome AF: 0.00908

Gnomad ASJ exome AF: 0.00364

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00264

Gnomad NFE exome AF: 0.0153

Gnomad OTH exome AF: 0.00971

GnomAD4 exome AF: 0.0125 AC: 15766 AN: 1256328 Hom.: 123 Cov.: 17 AF XY: 0.0120 AC XY: 7620 AN XY: 634438

African (AFR) AF: 0.00240 AC: 69 AN: 28722

American (AMR) AF: 0.00908 AC: 395 AN: 43522

Ashkenazi Jewish (ASJ) AF: 0.00417 AC: 103 AN: 24686

East Asian (EAS) AF: 0.00 AC: 0 AN: 37662

South Asian (SAS) AF: 0.000273 AC: 22 AN: 80702

European-Finnish (FIN) AF: 0.00334 AC: 171 AN: 51126

Middle Eastern (MID) AF: 0.00469 AC: 25 AN: 5326

European-Non Finnish (NFE) AF: 0.0154 AC: 14356 AN: 931452

Other (OTH) AF: 0.0118 AC: 625 AN: 53130

GnomAD4 genome AF: 0.00922 AC: 1402 AN: 152120 Hom.: 13 Cov.: 32 AF XY: 0.00892 AC XY: 663 AN XY: 74362

African (AFR) AF: 0.00248 AC: 103 AN: 41570

American (AMR) AF: 0.0134 AC: 205 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00490 AC: 17 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5194

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4826

European-Finnish (FIN) AF: 0.00208 AC: 22 AN: 10602

Middle Eastern (MID) AF: 0.00342 AC: 1 AN: 292

European-Non Finnish (NFE) AF: 0.0152 AC: 1032 AN: 67864

Other (OTH) AF: 0.00903 AC: 19 AN: 2104

Alfa AF: 0.0114 Hom.: 1

Bravo AF: 0.0102

Asia WGS AF: 0.000869 AC: 3 AN: 3468

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	1.3
DANN	Benign	0.82
PhyloP100		-0.053
PromoterAI		-0.00070	Neutral
Mutation Taster		=100/0	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: rs138194402; hg19: chr3-97503750;