rs281865195

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM4BP6BS2

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

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:5B:2O:1

Conservation

PhyloP100: 1.38

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -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=3, not_provided=1, Likely_benign=1, Benign=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 link	c.1053_1064delTGCAGAGCCACC	p.Ala352_Pro355del	disruptive_inframe_deletion	Exon 6 of 6	ENST00000381129.8	NP_055151.3	Q9NZN9-1F1T0B6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AIPL1	ENST00000381129.8 link	c.1053_1064delTGCAGAGCCACC	p.Ala352_Pro355del	disruptive_inframe_deletion	Exon 6 of 6	1	NM_014336.5	ENSP00000370521.3		Q9NZN9-1

Frequencies

GnomAD3 genomes

AF:

0.000625

AC:

AN:

151970

Hom.:

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.000872

AC:

218

AN:

250120

AF XY:

0.000776

show subpopulations

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 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.:

AF XY:

0.000695

AC XY:

505

AN XY:

726818

show subpopulations

Gnomad4 AFR exome

AF:

0.0000896

AC:

AN:

33476

Gnomad4 AMR exome

AF:

0.000648

AC:

AN:

44720

Gnomad4 ASJ exome

AF:

0.0114

AC:

298

AN:

26124

Gnomad4 EAS exome

AF:

0.0000252

AC:

AN:

39696

Gnomad4 SAS exome

AF:

0.0000232

AC:

AN:

86246

Gnomad4 FIN exome

AF:

0.000171

AC:

AN:

52774

Gnomad4 NFE exome

AF:

0.000569

AC:

633

AN:

1111792

Gnomad4 Remaining exome

AF:

0.00118

AC:

AN:

60360

Heterozygous variant carriers

136

205

273

341

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Exome Het

Variant carriers

112

140

<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:

0.000625

AC:

AN:

152088

Hom.:

Cov.:

AF XY:

0.000524

AC XY:

AN XY:

74358

show subpopulations

Gnomad4 AFR

AF:

0.00

AC:

AN:

Gnomad4 AMR

AF:

0.000393

AC:

0.000393082

AN:

0.000393082

Gnomad4 ASJ

AF:

0.0104

AC:

0.0103746

AN:

0.0103746

Gnomad4 EAS

AF:

0.00

AC:

AN:

Gnomad4 SAS

AF:

0.00

AC:

AN:

Gnomad4 FIN

AF:

0.000283

AC:

0.000283072

AN:

0.000283072

Gnomad4 NFE

AF:

0.000706

AC:

0.000706256

AN:

0.000706256

Gnomad4 OTH

AF:

0.000950

AC:

0.000949668

AN:

0.000949668

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Genome Het

Genome Hom

Variant carriers

<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:

0.00160

Hom.:

Bravo

AF:

0.000631

EpiCase

AF:

0.000873

EpiControl

AF:

0.00107

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:5Benign:2Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

CONE-ROD DYSTROPHY, AIPL1-RELATED

Pathogenic:1Uncertain:1

Jun 01, 2000

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Jan 06, 2020

Reproductive Health Research and Development, BGI Genomics

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:curation

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:1Other:1

Retina International

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Mar 03, 2015

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Juvenile retinitis pigmentosa, AIPL1-related

Pathogenic:1

Jun 01, 2000

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

not specified

Uncertain:1

Mar 12, 2022

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

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Sep 06, 2024

PreventionGenetics, part of Exact Sciences

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

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. -

Retinitis pigmentosa;C1858386:Leber congenital amaurosis 4

Uncertain:1

Aug 26, 2020

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:research

- -

Retinal dystrophy

Uncertain:1

Jan 01, 2021

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

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Leber congenital amaurosis 4

Benign:1

Dec 30, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Mutation Taster

=11/189

disease causing (ClinVar)

Splicing

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over