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. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. 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

Publications

4 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: 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 VariationId is 5568.

BS2

High Homozygotes in GnomAdExome4 at 2 AR,AD gene

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
AIPL1	NM_014336.5	MANE Select	c.1053_1064delTGCAGAGCCACC	p.Ala352_Pro355del	disruptive_inframe_deletion	Exon 6 of 6	NP_055151.3
AIPL1	NM_001285399.3		c.1017_1028delTGCAGAGCCACC	p.Ala340_Pro343del	disruptive_inframe_deletion	Exon 6 of 6	NP_001272328.1	Q7Z3H1
AIPL1	NM_001285400.3		c.987_998delTGCAGAGCCACC	p.Ala330_Pro333del	disruptive_inframe_deletion	Exon 6 of 6	NP_001272329.1	Q9NZN9-4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
AIPL1	ENST00000381129.8	TSL:1 MANE Select	c.1053_1064delTGCAGAGCCACC	p.Ala352_Pro355del	disruptive_inframe_deletion	Exon 6 of 6	ENSP00000370521.3	Q9NZN9-1
AIPL1	ENST00000574506.5	TSL:1	c.1017_1028delTGCAGAGCCACC	p.Ala340_Pro343del	disruptive_inframe_deletion	Exon 6 of 6	ENSP00000458456.1	Q7Z3H1
AIPL1	ENST00000570466.5	TSL:1	c.987_998delTGCAGAGCCACC	p.Ala330_Pro333del	disruptive_inframe_deletion	Exon 6 of 6	ENSP00000461287.1	Q9NZN9-4

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

African (AFR)

AF:

0.0000896

AC:

AN:

33476

American (AMR)

AF:

0.000648

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.0114

AC:

298

AN:

26124

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39696

South Asian (SAS)

AF:

0.0000232

AC:

AN:

86246

European-Finnish (FIN)

AF:

0.000171

AC:

AN:

52774

Middle Eastern (MID)

AF:

0.000174

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.000569

AC:

633

AN:

1111792

Other (OTH)

AF:

0.00118

AC:

AN:

60360

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.455

Heterozygous variant carriers

136

205

273

341

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

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

African (AFR)

AF:

0.00

AC:

AN:

41506

American (AMR)

AF:

0.000393

AC:

AN:

15264

Ashkenazi Jewish (ASJ)

AF:

0.0104

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5160

South Asian (SAS)

AF:

0.00

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.000283

AC:

AN:

10598

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.000706

AC:

AN:

67964

Other (OTH)

AF:

0.000950

AC:

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

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

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

CONE-ROD DYSTROPHY, AIPL1-RELATED (2)

AIPL1-related disorder (1)

Juvenile retinitis pigmentosa, AIPL1-related (1)

Leber congenital amaurosis 4 (1)

not provided (2)

not specified (1)

Retinal dystrophy (1)

Retinitis pigmentosa;C1858386:Leber congenital amaurosis 4 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

1.4

Mutation Taster

=11/189

disease causing (ClinVar)

(source)

Splicing

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over