rs62637016

Positions:

• chr17-6425603-GCT-G

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The NM_014336.5(AIPL1):​c.1010_1011del​(p.Glu337AlafsTer70) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: AIPL1 NM_014336.5 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3 O:1
• Conservation: PhyloP100: 0.446

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 Pathogenic. Variant got 14 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.126 CDS is truncated, and there are 3 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-6425603-GCT-G is Pathogenic according to our data. Variant chr17-6425603-GCT-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 5566.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-6425603-GCT-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AIPL1	NM_014336.5	c.1010_1011del	p.Glu337AlafsTer70	frameshift_variant	6/6	ENST00000381129.8	NP_055151.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AIPL1	ENST00000381129.8	c.1010_1011del	p.Glu337AlafsTer70	frameshift_variant	6/6	1	NM_014336.5	ENSP00000370521	P1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Leber congenital amaurosis 4 Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 2000	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 10, 2022	This frameshift has been observed in individual(s) with Leber congenital amaurosis (PMID: 10615133; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change results in a frameshift in the AIPL1 gene (p.Glu337Alafs*70). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 48 amino acid(s) of the AIPL1 protein and extend the protein by 21 additional amino acid residues. This variant is also known as Ala336Δ2 bp. For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:1 Other:1

not provided, no classification provided	literature only	Retina International	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -

Computational scores

Source: dbNSFP v4.3

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

LitVar

Other links and lift over

dbSNP: rs62637016; hg19: chr17-6328923;