rs12453262

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_014336.5(AIPL1):c.277-10A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.56 in 1,611,246 control chromosomes in the GnomAD database, including 256,149 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.53 ( 21911 hom., cov: 34)

Exomes 𝑓: 0.56 ( 234238 hom. )

Consequence

AIPL1
NM_014336.5 intron

Scores

Splicing: ADA: 0.00001746

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10O:1

Conservation

PhyloP100: -0.0900

Publications

11 publications found

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 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

AIPL1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.88).

BP6

Variant 17-6428516-T-G is Benign according to our data. Variant chr17-6428516-T-G is described in ClinVar as [Likely_benign]. Clinvar id is 99796.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.601 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AIPL1	NM_014336.5 link	c.277-10A>C		intron_variant	Intron 2 of 5	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.277-10A>C		intron_variant	Intron 2 of 5	1	NM_014336.5	ENSP00000370521.3		Q9NZN9-1

Frequencies

GnomAD3 genomes

AF:

0.527

AC:

80055

AN:

151996

Hom.:

21901

Cov.:

show subpopulations

Gnomad AFR

AF:

0.383

Gnomad AMI

AF:

0.462

Gnomad AMR

AF:

0.611

Gnomad ASJ

AF:

0.716

Gnomad EAS

AF:

0.497

Gnomad SAS

AF:

0.516

Gnomad FIN

AF:

0.551

Gnomad MID

AF:

0.747

Gnomad NFE

AF:

0.583

Gnomad OTH

AF:

0.590

GnomAD2 exomes

AF:

0.566

AC:

141360

AN:

249608

AF XY:

0.567

show subpopulations

Gnomad AFR exome

AF:

0.377

Gnomad AMR exome

AF:

0.656

Gnomad ASJ exome

AF:

0.720

Gnomad EAS exome

AF:

0.504

Gnomad FIN exome

AF:

0.552

Gnomad NFE exome

AF:

0.577

Gnomad OTH exome

AF:

0.600

GnomAD4 exome

AF:

0.564

AC:

822435

AN:

1459132

Hom.:

234238

Cov.:

AF XY:

0.563

AC XY:

409098

AN XY:

726038

show subpopulations

African (AFR)

AF:

0.377

AC:

12583

AN:

33420

American (AMR)

AF:

0.649

AC:

29025

AN:

44708

Ashkenazi Jewish (ASJ)

AF:

0.722

AC:

18846

AN:

26116

East Asian (EAS)

AF:

0.497

AC:

19736

AN:

39678

South Asian (SAS)

AF:

0.522

AC:

45004

AN:

86192

European-Finnish (FIN)

AF:

0.549

AC:

28999

AN:

52862

Middle Eastern (MID)

AF:

0.713

AC:

4113

AN:

5768

European-Non Finnish (NFE)

AF:

0.567

AC:

629567

AN:

1110088

Other (OTH)

AF:

0.573

AC:

34562

AN:

60300

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.442

Heterozygous variant carriers

19782

39564

59347

79129

98911

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

17364

34728

52092

69456

86820

<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:

0.527

AC:

80107

AN:

152114

Hom.:

21911

Cov.:

AF XY:

0.525

AC XY:

39051

AN XY:

74330

show subpopulations

African (AFR)

AF:

0.384

AC:

15922

AN:

41510

American (AMR)

AF:

0.611

AC:

9344

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.716

AC:

2483

AN:

3468

East Asian (EAS)

AF:

0.496

AC:

2554

AN:

5154

South Asian (SAS)

AF:

0.516

AC:

2492

AN:

4826

European-Finnish (FIN)

AF:

0.551

AC:

5832

AN:

10590

Middle Eastern (MID)

AF:

0.748

AC:

220

AN:

294

European-Non Finnish (NFE)

AF:

0.583

AC:

39598

AN:

67970

Other (OTH)

AF:

0.589

AC:

1242

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1954

3907

5861

7814

9768

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

700

1400

2100

2800

3500

<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:

0.578

Hom.:

44144

Bravo

AF:

0.526

Asia WGS

AF:

0.486

AC:

1691

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Jun 07, 2025

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

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 20, 2015

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2Other:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Retina International

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Leber congenital amaurosis 4

Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Retinitis Pigmentosa, Recessive

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Retinitis pigmentosa;C1858386:Leber congenital amaurosis 4

Benign:1

Aug 11, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Retinitis pigmentosa

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.88

CADD

Benign

2.5

(source)

DANN

Benign

0.69

PhyloP100

-0.090

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000017

dbscSNV1_RF

Benign

0.0020

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over