rs12449580

Positions:

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBA1

The NM_014336.5(AIPL1):c.268G>C(p.Asp90His) variant causes a missense change. The variant allele was found at a frequency of 0.199 in 1,603,474 control chromosomes in the GnomAD database, including 33,640 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.19 ( 2802 hom., cov: 30)

Exomes 𝑓: 0.20 ( 30838 hom. )

Consequence

AIPL1
NM_014336.5 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 4.71

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 made for transcript

Verdict is Benign. Variant got -18 ACMG points.

PM1

In a domain PPIase FKBP-type (size 92) in uniprot entity AIPL1_HUMAN there are 18 pathogenic changes around while only 4 benign (82%) in NM_014336.5

BP4

Computational evidence support a benign effect (MetaRNN=0.0016991198).

BP6

Variant 17-6433927-C-G is Benign according to our data. Variant chr17-6433927-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 99794.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-6433927-C-G is described in Lovd as [Benign]. Variant chr17-6433927-C-G is described in Lovd as [Likely_pathogenic].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.316 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AIPL1	NM_014336.5 linkuse as main transcript	c.268G>C	p.Asp90His	missense_variant	2/6	ENST00000381129.8	NP_055151.3	Q9NZN9-1F1T0B6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AIPL1	ENST00000381129.8 linkuse as main transcript	c.268G>C	p.Asp90His	missense_variant	2/6	1	NM_014336.5	ENSP00000370521.3		Q9NZN9-1

Frequencies

GnomAD3 genomes

AF:

0.187

AC:

27366

AN:

146644

Hom.:

2803

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0965

Gnomad AMI

AF:

0.0902

Gnomad AMR

AF:

0.213

Gnomad ASJ

AF:

0.271

Gnomad EAS

AF:

0.330

Gnomad SAS

AF:

0.109

Gnomad FIN

AF:

0.266

Gnomad MID

AF:

0.361

Gnomad NFE

AF:

0.207

Gnomad OTH

AF:

0.234

GnomAD3 exomes

AF:

0.209

AC:

52103

AN:

249150

Hom.:

6017

AF XY:

0.204

AC XY:

27526

AN XY:

134720

show subpopulations

Gnomad AFR exome

AF:

0.0833

Gnomad AMR exome

AF:

0.256

Gnomad ASJ exome

AF:

0.293

Gnomad EAS exome

AF:

0.328

Gnomad SAS exome

AF:

0.111

Gnomad FIN exome

AF:

0.248

Gnomad NFE exome

AF:

0.204

Gnomad OTH exome

AF:

0.223

GnomAD4 exome

AF:

0.200

AC:

291904

AN:

1456726

Hom.:

30838

Cov.:

AF XY:

0.199

AC XY:

144384

AN XY:

724780

show subpopulations

Gnomad4 AFR exome

AF:

0.0863

Gnomad4 AMR exome

AF:

0.249

Gnomad4 ASJ exome

AF:

0.291

Gnomad4 EAS exome

AF:

0.355

Gnomad4 SAS exome

AF:

0.112

Gnomad4 FIN exome

AF:

0.242

Gnomad4 NFE exome

AF:

0.198

Gnomad4 OTH exome

AF:

0.205

GnomAD4 genome

AF:

0.186

AC:

27356

AN:

146748

Hom.:

2802

Cov.:

AF XY:

0.188

AC XY:

13496

AN XY:

71810

show subpopulations

Gnomad4 AFR

AF:

0.0963

Gnomad4 AMR

AF:

0.213

Gnomad4 ASJ

AF:

0.271

Gnomad4 EAS

AF:

0.329

Gnomad4 SAS

AF:

0.110

Gnomad4 FIN

AF:

0.266

Gnomad4 NFE

AF:

0.207

Gnomad4 OTH

AF:

0.230

Alfa

AF:

0.201

Hom.:

2693

Bravo

AF:

0.178

TwinsUK

AF:

0.186

AC:

688

ALSPAC

AF:

0.192

AC:

740

ESP6500AA

AF:

0.0869

AC:

383

ESP6500EA

AF:

0.206

AC:

1768

ExAC

AF:

0.200

AC:

24239

Asia WGS

AF:

0.200

AC:

693

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 provided

Benign:3Other:1

not provided, no classification provided	literature only	Retina International	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Leber congenital amaurosis 4

Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

- -

Leber congenital amaurosis 1

Benign:1

Benign, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

Retinitis pigmentosa;C1858386:Leber congenital amaurosis 4

Benign:1

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Sep 20, 2021

- -

Retinitis Pigmentosa, Dominant

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Retinitis pigmentosa

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.75

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Uncertain

0.040

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.37

T;.;T;.;.;.;T;T

Eigen

Benign

0.16

Eigen_PC

Uncertain

0.23

FATHMM_MKL

Uncertain

0.97

LIST_S2

Benign

0.81

T;T;T;T;T;T;T;T

MetaRNN

Benign

0.0017

T;T;T;T;T;T;T;T

MetaSVM

Benign

-1.2

MutationAssessor

Benign

1.9

M;M;.;.;.;M;.;.

PrimateAI

Uncertain

0.55

PROVEAN

Pathogenic

-5.6

D;D;.;.;.;.;.;.

REVEL

Uncertain

0.61

Sift

Benign

0.057

T;D;.;.;.;.;.;.

Sift4G

Uncertain

0.0070

D;D;D;T;D;D;T;.

Polyphen

0.71

P;D;.;B;.;.;.;.

Vest4

0.31

MPC

0.63

ClinPred

0.036

GERP RS

4.0

Varity_R

0.67

gMVP

0.84

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

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