NM_001278293.3:c.186-18T>C

Variant names:

• chr3-97780597-T-C
• rs77906443
• NM_001278293.3:c.186-18T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001278293.3(ARL6):​c.186-18T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0193 in 1,604,612 control chromosomes in the GnomAD database, including 577 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.039 (207 hom., cov: 32)
  • Exomes 𝑓: 0.017 (370 hom.)
• Consequence: ARL6 NM_001278293.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.0630
• Publications: 3 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: 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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 3-97780597-T-C is Benign according to our data. Variant chr3-97780597-T-C is described in ClinVar as Benign. ClinVar VariationId is 262014.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0923 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARL6	NM_001278293.3	MANE Select	c.186-18T>C		intron	N/A	NP_001265222.1
	ARL6	NM_001323513.2		c.186-18T>C		intron	N/A	NP_001310442.1
	ARL6	NM_032146.5		c.186-18T>C		intron	N/A	NP_115522.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARL6	ENST00000463745.6	TSL:2 MANE Select	c.186-18T>C		intron	N/A	ENSP00000419619.1
	ARL6	ENST00000493990.5	TSL:1	n.186-18T>C		intron	N/A	ENSP00000418057.1
	ARL6	ENST00000496713.1	TSL:1	n.424-18T>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0386 AC: 5867 AN: 152122 Hom.: 207 Cov.: 32

Gnomad AFR AF: 0.0951

Gnomad AMI AF: 0.0296

Gnomad AMR AF: 0.0290

Gnomad ASJ AF: 0.0421

Gnomad EAS AF: 0.0358

Gnomad SAS AF: 0.0139

Gnomad FIN AF: 0.00170

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0141

Gnomad OTH AF: 0.0349

GnomAD2 exomes AF: 0.0218 AC: 5473 AN: 251108 AF XY: 0.0202

Gnomad AFR exome AF: 0.0999

Gnomad AMR exome AF: 0.0172

Gnomad ASJ exome AF: 0.0452

Gnomad EAS exome AF: 0.0396

Gnomad FIN exome AF: 0.00231

Gnomad NFE exome AF: 0.0134

Gnomad OTH exome AF: 0.0194

GnomAD4 exome AF: 0.0172 AC: 25035 AN: 1452372 Hom.: 370 Cov.: 29 AF XY: 0.0171 AC XY: 12374 AN XY: 723358

African (AFR) AF: 0.0970 AC: 3222 AN: 33214

American (AMR) AF: 0.0174 AC: 779 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.0469 AC: 1221 AN: 26038

East Asian (EAS) AF: 0.0290 AC: 1144 AN: 39480

South Asian (SAS) AF: 0.0124 AC: 1063 AN: 86030

European-Finnish (FIN) AF: 0.00260 AC: 139 AN: 53396

Middle Eastern (MID) AF: 0.0231 AC: 133 AN: 5750

European-Non Finnish (NFE) AF: 0.0144 AC: 15946 AN: 1103716

Other (OTH) AF: 0.0231 AC: 1388 AN: 60050

GnomAD4 genome AF: 0.0385 AC: 5866 AN: 152240 Hom.: 207 Cov.: 32 AF XY: 0.0380 AC XY: 2832 AN XY: 74438

African (AFR) AF: 0.0948 AC: 3939 AN: 41544

American (AMR) AF: 0.0289 AC: 441 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.0421 AC: 146 AN: 3470

East Asian (EAS) AF: 0.0359 AC: 186 AN: 5184

South Asian (SAS) AF: 0.0139 AC: 67 AN: 4828

European-Finnish (FIN) AF: 0.00170 AC: 18 AN: 10616

Middle Eastern (MID) AF: 0.0306 AC: 9 AN: 294

European-Non Finnish (NFE) AF: 0.0141 AC: 961 AN: 67996

Other (OTH) AF: 0.0341 AC: 72 AN: 2112

Alfa AF: 0.0256 Hom.: 31

Bravo AF: 0.0438

Asia WGS AF: 0.0280 AC: 98 AN: 3470

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	1	Bardet-Biedl syndrome 3;C3150808:Retinitis pigmentosa 55 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.45
DANN	Benign	0.65
PhyloP100		-0.063
PromoterAI		0.0013	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs77906443; hg19: chr3-97499441; COSMIC: COSV60117207; COSMIC: COSV60117207;