17-6425830-CC-GA

Variant names:

• chr17-6425830-CC-GA
• ENST00000575265.5:c.*755_*756delGGinsTC

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PVS1

The NM_014336.5(AIPL1):​c.785-1_785delGGinsTC​(p.Gly262Ala) variant causes a splice acceptor, missense, splice region, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G262S) has been classified as Pathogenic. The gene AIPL1 is included in the ClinGen Criteria Specification Registry.

• Frequency: Genomes: not found (cov: 32)
• Consequence: AIPL1 NM_014336.5 splice_acceptor, missense, splice_region, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.26
• Publications: 0 publications found

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]

AIPL1 Gene-Disease associations (from GenCC):

• AIPL1-related retinopathy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• Leber congenital amaurosis 4

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• Leber congenital amaurosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Specifications for AIPL1 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease,

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014336.5. 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
	AIPL1	NM_014336.5	MANE Select	c.785-1_785delGGinsTC	p.Gly262Ala	splice_acceptor missense splice_region intron	N/A	NP_055151.3
	AIPL1	NM_001285403.4		c.*755_*756delGGinsTC		3_prime_UTR	Exon 5 of 5	NP_001272332.1	F1T0B5
	AIPL1	NM_001285399.3		c.749-1_749delGGinsTC	p.Gly250Ala	splice_acceptor missense splice_region intron	N/A	NP_001272328.1	Q7Z3H1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AIPL1	ENST00000575265.5	TSL:1	c.*755_*756delGGinsTC		3_prime_UTR	Exon 5 of 5	ENSP00000459673.1	F1T0C4
	AIPL1	ENST00000381129.8	TSL:1 MANE Select	c.785-1_785delGGinsTC	p.Gly262Ala	splice_acceptor missense splice_region intron	N/A	ENSP00000370521.3	Q9NZN9-1
	AIPL1	ENST00000574506.5	TSL:1	c.749-1_749delGGinsTC	p.Gly250Ala	splice_acceptor missense splice_region intron	N/A	ENSP00000458456.1	Q7Z3H1

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

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr17-6329150;