NM_014336.5:c.267C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6BP7BS1BS2

The NM_014336.5(AIPL1):​c.267C>T​(p.Cys89Cys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00493 in 1,613,722 control chromosomes in the GnomAD database, including 31 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0035 ( 2 hom., cov: 30)
Exomes 𝑓: 0.0051 ( 29 hom. )

Consequence

AIPL1
NM_014336.5 synonymous

Scores

2

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:6O:1

Conservation

PhyloP100: -0.523

Publications

3 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

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -14 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.71).
BP6
Variant 17-6433928-G-A is Benign according to our data. Variant chr17-6433928-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 95582.
BP7
Synonymous conserved (PhyloP=-0.523 with no splicing effect.
BS1
Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00355 (540/152258) while in subpopulation NFE AF = 0.0052 (354/68028). AF 95% confidence interval is 0.00476. There are 2 homozygotes in GnomAd4. There are 229 alleles in the male GnomAd4 subpopulation. Median coverage is 30. This position passed quality control check.
BS2
High Homozygotes in GnomAd4 at 2 AR,AD gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
AIPL1NM_014336.5 linkc.267C>T p.Cys89Cys synonymous_variant Exon 2 of 6 ENST00000381129.8 NP_055151.3 Q9NZN9-1F1T0B6

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
AIPL1ENST00000381129.8 linkc.267C>T p.Cys89Cys synonymous_variant Exon 2 of 6 1 NM_014336.5 ENSP00000370521.3 Q9NZN9-1

Frequencies

GnomAD3 genomes
AF:
0.00356
AC:
541
AN:
152140
Hom.:
2
Cov.:
30
show subpopulations
Gnomad AFR
AF:
0.00109
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00183
Gnomad ASJ
AF:
0.0153
Gnomad EAS
AF:
0.000774
Gnomad SAS
AF:
0.000208
Gnomad FIN
AF:
0.00452
Gnomad MID
AF:
0.00633
Gnomad NFE
AF:
0.00522
Gnomad OTH
AF:
0.00239
GnomAD2 exomes
AF:
0.00417
AC:
1043
AN:
250336
AF XY:
0.00407
show subpopulations
Gnomad AFR exome
AF:
0.000618
Gnomad AMR exome
AF:
0.00171
Gnomad ASJ exome
AF:
0.0129
Gnomad EAS exome
AF:
0.000109
Gnomad FIN exome
AF:
0.00559
Gnomad NFE exome
AF:
0.00595
Gnomad OTH exome
AF:
0.00344
GnomAD4 exome
AF:
0.00508
AC:
7422
AN:
1461464
Hom.:
29
Cov.:
33
AF XY:
0.00500
AC XY:
3634
AN XY:
726972
show subpopulations
African (AFR)
AF:
0.000628
AC:
21
AN:
33466
American (AMR)
AF:
0.00166
AC:
74
AN:
44694
Ashkenazi Jewish (ASJ)
AF:
0.0128
AC:
334
AN:
26130
East Asian (EAS)
AF:
0.000101
AC:
4
AN:
39692
South Asian (SAS)
AF:
0.000812
AC:
70
AN:
86158
European-Finnish (FIN)
AF:
0.00569
AC:
304
AN:
53394
Middle Eastern (MID)
AF:
0.000880
AC:
5
AN:
5680
European-Non Finnish (NFE)
AF:
0.00565
AC:
6286
AN:
1111878
Other (OTH)
AF:
0.00537
AC:
324
AN:
60372
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.476
Heterozygous variant carriers
0
424
848
1271
1695
2119
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Exome Hom
Variant carriers
0
222
444
666
888
1110
<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:
0.00355
AC:
540
AN:
152258
Hom.:
2
Cov.:
30
AF XY:
0.00308
AC XY:
229
AN XY:
74434
show subpopulations
African (AFR)
AF:
0.00108
AC:
45
AN:
41560
American (AMR)
AF:
0.00183
AC:
28
AN:
15296
Ashkenazi Jewish (ASJ)
AF:
0.0153
AC:
53
AN:
3472
East Asian (EAS)
AF:
0.000776
AC:
4
AN:
5154
South Asian (SAS)
AF:
0.000208
AC:
1
AN:
4812
European-Finnish (FIN)
AF:
0.00452
AC:
48
AN:
10614
Middle Eastern (MID)
AF:
0.00680
AC:
2
AN:
294
European-Non Finnish (NFE)
AF:
0.00520
AC:
354
AN:
68028
Other (OTH)
AF:
0.00236
AC:
5
AN:
2116
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.505
Heterozygous variant carriers
0
29
59
88
118
147
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
10
20
30
40
50
<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:
0.00590
Hom.:
0
Bravo
AF:
0.00342
Asia WGS
AF:
0.000866
AC:
3
AN:
3478
EpiCase
AF:
0.00491
EpiControl
AF:
0.00428

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:4Benign:6Other:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Benign:3Other:1
-
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Significance:Likely benign
Review Status:no assertion criteria provided
Collection Method:clinical testing

- -

-
Retina International
Significance:not provided
Review Status:no classification provided
Collection Method:literature only

- -

Jul 01, 2024
CeGaT Center for Human Genetics Tuebingen
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

AIPL1: BP4, BP7, BS2 -

Aug 15, 2023
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Leber congenital amaurosis 4 Uncertain:1Benign:1
Jan 12, 2018
Illumina Laboratory Services, Illumina
Significance:Uncertain significance
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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Jan 23, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

not specified Benign:2
Sep 19, 2016
Eurofins Ntd Llc (ga)
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

-
Clinical Genetics, Academic Medical Center
Significance:Benign
Review Status:no assertion criteria provided
Collection Method:clinical testing

- -

Retinitis Pigmentosa, Recessive Uncertain:1
Jun 14, 2016
Illumina Laboratory Services, Illumina
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Retinal dystrophy Uncertain:1
Jan 01, 2012
Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg
Significance:Uncertain significance
Review Status:no assertion criteria provided
Collection Method:clinical testing

- -

Retinitis Pigmentosa, Dominant Uncertain:1
Jun 14, 2016
Illumina Laboratory Services, Illumina
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.71
CADD
Benign
1.6
DANN
Benign
0.68
PhyloP100
-0.52
Mutation Taster
=99/1
polymorphism

Splicing

Name
Calibrated prediction
Score
Prediction
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

Other links and lift over

dbSNP: rs62653020; hg19: chr17-6337248; API