rs925615

Positions:

• chr17-6427083-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_014336.5(AIPL1):​c.466-26T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0764 in 1,613,450 control chromosomes in the GnomAD database, including 4,977 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.065 (358 hom., cov: 32)
  • Exomes 𝑓: 0.078 (4619 hom.)
• Consequence: AIPL1 NM_014336.5 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.140

Genes affected

AIPL1 (HGNC:359): (aryl hydrocarbon receptor interacting protein like 1) Leber congenital amaurosis (LCA) is the most severe inherited retinopathy with the earliest age of onset and accounts for at least 5% of all inherited retinal diseases. Affected individuals are diagnosed at birth or in the first few months of life with nystagmus, severely impaired vision or blindness and an abnormal or flat electroretinogram. The photoreceptor/pineal-expressed gene, AIPL1, encoding aryl-hydrocarbon interacting protein-like 1, is located within the LCA4 candidate region. The encoded protein contains three tetratricopeptide motifs, consistent with chaperone or nuclear transport activity. Mutations in this gene may cause approximately 20% of recessive LCA. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2014]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: This place is a probable branch point but rather VUS (scored 4 / 10). Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 17-6427083-A-G is Benign according to our data. Variant chr17-6427083-A-G is described in ClinVar as [Benign]. Clinvar id is 1245637.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr17-6427083-A-G is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0825 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AIPL1	NM_014336.5	c.466-26T>C		intron_variant		ENST00000381129.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AIPL1	ENST00000381129.8	c.466-26T>C		intron_variant		1	NM_014336.5	P1

Frequencies

GnomAD3 genomes AF: 0.0652 AC: 9917 AN: 152112 Hom.: 358 Cov.: 32

Gnomad AFR AF: 0.0573

Gnomad AMI AF: 0.0746

Gnomad AMR AF: 0.0380

Gnomad ASJ AF: 0.0550

Gnomad EAS AF: 0.0892

Gnomad SAS AF: 0.0550

Gnomad FIN AF: 0.0425

Gnomad MID AF: 0.0759

Gnomad NFE AF: 0.0791

Gnomad OTH AF: 0.0580

GnomAD3 exomes AF: 0.0628 AC: 15760 AN: 250826 Hom.: 586 AF XY: 0.0638 AC XY: 8645 AN XY: 135586

Gnomad AFR exome AF: 0.0541

Gnomad AMR exome AF: 0.0272

Gnomad ASJ exome AF: 0.0546

Gnomad EAS exome AF: 0.0858

Gnomad SAS exome AF: 0.0567

Gnomad FIN exome AF: 0.0398

Gnomad NFE exome AF: 0.0778

Gnomad OTH exome AF: 0.0658

GnomAD4 exome AF: 0.0775 AC: 113274 AN: 1461220 Hom.: 4619 Cov.: 36 AF XY: 0.0767 AC XY: 55784 AN XY: 726908

Gnomad4 AFR exome AF: 0.0566

Gnomad4 AMR exome AF: 0.0285

Gnomad4 ASJ exome AF: 0.0559

Gnomad4 EAS exome AF: 0.0760

Gnomad4 SAS exome AF: 0.0569

Gnomad4 FIN exome AF: 0.0430

Gnomad4 NFE exome AF: 0.0840

Gnomad4 OTH exome AF: 0.0766

GnomAD4 genome AF: 0.0652 AC: 9922 AN: 152230 Hom.: 358 Cov.: 32 AF XY: 0.0635 AC XY: 4729 AN XY: 74430

Gnomad4 AFR AF: 0.0573

Gnomad4 AMR AF: 0.0380

Gnomad4 ASJ AF: 0.0550

Gnomad4 EAS AF: 0.0892

Gnomad4 SAS AF: 0.0552

Gnomad4 FIN AF: 0.0425

Gnomad4 NFE AF: 0.0791

Gnomad4 OTH AF: 0.0573

Alfa AF: 0.0710 Hom.: 84

Bravo AF: 0.0644

Asia WGS AF: 0.0740 AC: 258 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	8.0
DANN	Benign	0.80
BranchPoint Hunter		4.0

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: rs925615; hg19: chr17-6330403;