17-6426748-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_014336.5(AIPL1):c.651A>G(p.Pro217Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.737 in 1,613,650 control chromosomes in the GnomAD database, including 439,818 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★). Synonymous variant affecting the same amino acid position (i.e. P217P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.73 ( 41112 hom., cov: 33)

Exomes 𝑓: 0.74 ( 398706 hom. )

Consequence

AIPL1
NM_014336.5 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11O:1

Conservation

PhyloP100: -2.52

Publications

24 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.83).

BP6

Variant 17-6426748-T-C is Benign according to our data. Variant chr17-6426748-T-C is described in ClinVar as Benign. ClinVar VariationId is 99805.Status of the report is reviewed_by_expert_panel, 3 stars.

BP7

Synonymous conserved (PhyloP=-2.52 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.746 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AIPL1	NM_014336.5 link	c.651A>G	p.Pro217Pro	synonymous_variant	Exon 5 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.651A>G	p.Pro217Pro	synonymous_variant	Exon 5 of 6	1	NM_014336.5	ENSP00000370521.3		Q9NZN9-1

Frequencies

GnomAD3 genomes

AF:

0.734

AC:

111557

AN:

152020

Hom.:

41079

Cov.:

show subpopulations

Gnomad AFR

AF:

0.727

Gnomad AMI

AF:

0.659

Gnomad AMR

AF:

0.741

Gnomad ASJ

AF:

0.828

Gnomad EAS

AF:

0.672

Gnomad SAS

AF:

0.665

Gnomad FIN

AF:

0.662

Gnomad MID

AF:

0.880

Gnomad NFE

AF:

0.751

Gnomad OTH

AF:

0.772

GnomAD2 exomes

AF:

0.728

AC:

182942

AN:

251182

AF XY:

0.727

show subpopulations

Gnomad AFR exome

AF:

0.724

Gnomad AMR exome

AF:

0.753

Gnomad ASJ exome

AF:

0.831

Gnomad EAS exome

AF:

0.674

Gnomad FIN exome

AF:

0.660

Gnomad NFE exome

AF:

0.748

Gnomad OTH exome

AF:

0.756

GnomAD4 exome

AF:

0.738

AC:

1077902

AN:

1461512

Hom.:

398706

Cov.:

AF XY:

0.736

AC XY:

535310

AN XY:

727068

show subpopulations

African (AFR)

AF:

0.726

AC:

24293

AN:

33480

American (AMR)

AF:

0.750

AC:

33532

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.834

AC:

21783

AN:

26130

East Asian (EAS)

AF:

0.664

AC:

26344

AN:

39700

South Asian (SAS)

AF:

0.680

AC:

58619

AN:

86258

European-Finnish (FIN)

AF:

0.660

AC:

35064

AN:

53128

Middle Eastern (MID)

AF:

0.868

AC:

5009

AN:

5768

European-Non Finnish (NFE)

AF:

0.745

AC:

828121

AN:

1111938

Other (OTH)

AF:

0.747

AC:

45137

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

18640

37279

55919

74558

93198

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

20164

40328

60492

80656

100820

<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:

0.734

AC:

111649

AN:

152138

Hom.:

41112

Cov.:

AF XY:

0.728

AC XY:

54123

AN XY:

74376

show subpopulations

African (AFR)

AF:

0.728

AC:

30205

AN:

41506

American (AMR)

AF:

0.741

AC:

11328

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.828

AC:

2874

AN:

3472

East Asian (EAS)

AF:

0.670

AC:

3451

AN:

5148

South Asian (SAS)

AF:

0.665

AC:

3208

AN:

4822

European-Finnish (FIN)

AF:

0.662

AC:

7013

AN:

10592

Middle Eastern (MID)

AF:

0.884

AC:

260

AN:

294

European-Non Finnish (NFE)

AF:

0.751

AC:

51080

AN:

67984

Other (OTH)

AF:

0.770

AC:

1630

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

1560

3119

4679

6238

7798

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

846

1692

2538

3384

4230

<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:

0.748

Hom.:

166950

Bravo

AF:

0.741

Asia WGS

AF:

0.661

AC:

2298

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:3Other:1

Retina International

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Nov 29, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Leber congenital amaurosis 4

Benign:2

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. -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Retinitis Pigmentosa, Dominant

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Likely 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

-0.83

CADD

Benign

5.0

(source)

DANN

Benign

0.51

PhyloP100

-2.5

Mutation Taster

=99/1

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.080

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