rs281865195

Variant names:

• chr17-6425550-GGGTGGCTCTGCA-G
• rs281865195
• NM_014336.5:c.1053_1064delTGCAGAGCCACC

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM4 BP6 BS2

The NM_014336.5(AIPL1):​c.1053_1064delTGCAGAGCCACC​(p.Ala352_Pro355del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000708 in 1,613,036 control chromosomes in the GnomAD database, including 3 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00062 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00072 (2 hom.)
• Consequence: AIPL1 NM_014336.5 disruptive_inframe_deletion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:4 B:2 O:1
• Conservation: PhyloP100: 1.38

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 Likely_benign. Variant got -3 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_014336.5.
• BP6: Variant 17-6425550-GGGTGGCTCTGCA-G is Benign according to our data. Variant chr17-6425550-GGGTGGCTCTGCA-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 5568.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Benign=1, Likely_benign=1, not_provided=1}.
• BS2: High Homozygotes in GnomAdExome4 at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AIPL1	NM_014336.5	c.1053_1064delTGCAGAGCCACC	p.Ala352_Pro355del	disruptive_inframe_deletion	Exon 6 of 6	ENST00000381129.8	NP_055151.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AIPL1	ENST00000381129.8	c.1053_1064delTGCAGAGCCACC	p.Ala352_Pro355del	disruptive_inframe_deletion	Exon 6 of 6	1	NM_014336.5	ENSP00000370521.3

Frequencies

GnomAD3 genomes AF: 0.000625 AC: 95 AN: 151970 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000394

Gnomad ASJ AF: 0.0104

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000706

Gnomad OTH AF: 0.000960

GnomAD3 exomes AF: 0.000872 AC: 218 AN: 250120 Hom.: 0 AF XY: 0.000776 AC XY: 105 AN XY: 135274

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000550

Gnomad ASJ exome AF: 0.0104

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.000189

Gnomad NFE exome AF: 0.000673

Gnomad OTH exome AF: 0.00180

GnomAD4 exome AF: 0.000717 AC: 1047 AN: 1460948 Hom.: 2 AF XY: 0.000695 AC XY: 505 AN XY: 726818

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.000648

Gnomad4 ASJ exome AF: 0.0114

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.000171

Gnomad4 NFE exome AF: 0.000569

Gnomad4 OTH exome AF: 0.00118

GnomAD4 genome AF: 0.000625 AC: 95 AN: 152088 Hom.: 1 Cov.: 32 AF XY: 0.000524 AC XY: 39 AN XY: 74358

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000393

Gnomad4 ASJ AF: 0.0104

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000283

Gnomad4 NFE AF: 0.000706

Gnomad4 OTH AF: 0.000950

Alfa AF: 0.00160 Hom.: 0

Bravo AF: 0.000631

EpiCase AF: 0.000873

EpiControl AF: 0.00107

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:4 Benign:2 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

CONE-ROD DYSTROPHY, AIPL1-RELATED Pathogenic:1 Uncertain:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 01, 2000	- -
Uncertain significance, no assertion criteria provided	curation	Reproductive Health Research and Development, BGI Genomics	Jan 06, 2020	NM_014336.3:c.1053_1064delTGCAGAGCCACC in the AIPL1 gene has an allele frequency of 0.01 in Ashkenazi Jewish subpopulation in the gnomAD database. It has been detected in two individuals with cone-rod dystrophy (PMID: 10873396). This in-frame deletion happens in a repetitive region without known function. We interpret it as variant of uncertain significance (VUS). ACMG/AMP criteria applied: BP3, PP4. -

not provided Benign:1 Other:1

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
not provided, no classification provided	literature only	Retina International	-	- -

Juvenile retinitis pigmentosa, AIPL1-related Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jun 01, 2000

- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Mar 12, 2022

Variant summary: AIPL1 c.1053_1064del12 (p.Ala352_Pro355del) results in an in-frame deletion that is predicted to remove four amino acids from the encoded protein. The variant allele was found at a frequency of 0.00087 in 250120 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in AIPL1 causing Leber Congenital Amaurosis (0.00087 vs 0.0011), allowing no conclusion about variant significance. Although reported in the literature, as unlikely to be associated with autosomal dominant Inherited Retinal Degeneration (example, Hanany_2019), to our knowledge, no penetrant association of c.1053_1064del12 in individuals affected with Autosomal Recessive Leber Congenital Amaurosis and no experimental evidence demonstrating its impact on protein function have been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (likely benign/benign, n=2; VUS, n=1). Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -

AIPL1-related disorder Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 06, 2024

The AIPL1 c.1053_1064del12 variant is predicted to result in an in-frame deletion (p.Ala352_Pro355del). This variant has been reported in the heterozygous state in individuals with autosomal dominant cone-rod dystrophy or juvenile retinitis pigmentosa (Sohocki et al. 2000. PubMed ID: 10873396; Sacristan-Reviriego et al. 2020. PubMed ID: 33067476). This deletion is located in the highly conserved "hinge region" of AIPL1, which is only present in primates (Sohocki et al. 2000. PubMed ID: 10873396). A transgenic mouse model has demonstrated a dominant negative effect on photoreceptors, leading to cone degeneration (Ku et al. 2015. PubMed ID: 25274777). In vitro functional studies revealed that this variant does not affect its cytoplasmic distribution, interaction with HSP90 or cGMP modulation; however these studies are not known to be informative for modeling of gain-of-function disease mechanisms (Sacristan-Reviriego et al 2020. PubMed ID: 33067476). Additionally, this variant is reported in 1.0% of alleles in individuals of Ashkenazi Jewish descent in gnomAD, which is likely too frequent to be a primary cause of disease. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Retinal dystrophy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg

Jan 01, 2021

- -

Leber congenital amaurosis 4 Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 30, 2024

- -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs281865195; hg19: chr17-6328870;