Genetic Variant NM_001278293.3:c.349+36G>A (chr3-97785085-G-A) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBS1BS2

The NM_001278293.3(ARL6):c.349+36G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00701 in 1,526,424 control chromosomes in the GnomAD database, including 69 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.0065 ( 6 hom., cov: 32)

Exomes 𝑓: 0.0071 ( 63 hom. )

Consequence

ARL6
NM_001278293.3 intron

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.690

Publications

0 publications found

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 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

ARL6 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.86).

BP6

Variant 3-97785085-G-A is Benign according to our data. Variant chr3-97785085-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 262016.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00649 (985/151842) while in subpopulation NFE AF = 0.0098 (665/67826). AF 95% confidence interval is 0.00919. There are 6 homozygotes in GnomAd4. There are 479 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 6 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARL6	NM_001278293.3 link	c.349+36G>A		intron_variant	Intron 5 of 7	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.349+36G>A		intron_variant	Intron 5 of 7	2	NM_001278293.3	ENSP00000419619.1		Q9H0F7-1

Frequencies

GnomAD3 genomes

AF:

0.00649

AC:

985

AN:

151726

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00119

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00151

Gnomad ASJ

AF:

0.0231

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000415

Gnomad FIN

AF:

0.0147

Gnomad MID

AF:

0.00637

Gnomad NFE

AF:

0.00980

Gnomad OTH

AF:

0.00431

GnomAD2 exomes

AF:

0.00667

AC:

1670

AN:

250422

AF XY:

0.00650

show subpopulations

Gnomad AFR exome

AF:

0.000927

Gnomad AMR exome

AF:

0.00212

Gnomad ASJ exome

AF:

0.0214

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0140

Gnomad NFE exome

AF:

0.00898

Gnomad OTH exome

AF:

0.00672

GnomAD4 exome

AF:

0.00707

AC:

9721

AN:

1374582

Hom.:

Cov.:

AF XY:

0.00703

AC XY:

4847

AN XY:

689258

show subpopulations

African (AFR)

AF:

0.000600

AC:

AN:

31688

American (AMR)

AF:

0.00209

AC:

AN:

44522

Ashkenazi Jewish (ASJ)

AF:

0.0235

AC:

598

AN:

25488

East Asian (EAS)

AF:

0.00

AC:

AN:

39100

South Asian (SAS)

AF:

0.000154

AC:

AN:

84370

European-Finnish (FIN)

AF:

0.0143

AC:

760

AN:

53244

Middle Eastern (MID)

AF:

0.00196

AC:

AN:

5620

European-Non Finnish (NFE)

AF:

0.00759

AC:

7841

AN:

1033162

Other (OTH)

AF:

0.00673

AC:

386

AN:

57388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

451

901

1352

1802

2253

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

228

456

684

912

1140

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00649

AC:

985

AN:

151842

Hom.:

Cov.:

AF XY:

0.00646

AC XY:

479

AN XY:

74202

show subpopulations

African (AFR)

AF:

0.00118

AC:

AN:

41460

American (AMR)

AF:

0.00151

AC:

AN:

15254

Ashkenazi Jewish (ASJ)

AF:

0.0231

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5166

South Asian (SAS)

AF:

0.000415

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.0147

AC:

155

AN:

10542

Middle Eastern (MID)

AF:

0.00685

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00980

AC:

665

AN:

67826

Other (OTH)

AF:

0.00427

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

146

195

244

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0103

Hom.:

Bravo

AF:

0.00513

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.86

CADD

Benign

0.31

(source)

DANN

Benign

0.56

PhyloP100

-0.69

PromoterAI

-0.016

Neutral

(source)

Mutation Taster

=100/0

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over