rs61757484

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_014336.5(AIPL1):c.1126C>T(p.Pro376Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00336 in 1,605,510 control chromosomes in the GnomAD database, including 170 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.018 ( 89 hom., cov: 32)

Exomes 𝑓: 0.0019 ( 81 hom. )

Consequence

AIPL1
NM_014336.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10O:2

Conservation

PhyloP100: -4.46

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0032194257).

BP6

Variant 17-6425489-G-A is Benign according to our data. Variant chr17-6425489-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 65708.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-6425489-G-A is described in Lovd as [Benign]. Variant chr17-6425489-G-A is described in Lovd as [Pathogenic]. Variant chr17-6425489-G-A is described in Lovd as [Likely_benign]. Variant chr17-6425489-G-A is described in Lovd as [Likely_pathogenic].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0589 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.1126C>T	p.Pro376Ser	missense_variant	6/6	ENST00000381129.8	NP_055151.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AIPL1	ENST00000381129.8 linkuse as main transcript	c.1126C>T	p.Pro376Ser	missense_variant	6/6	1	NM_014336.5	ENSP00000370521	P1	Q9NZN9-1

Frequencies

GnomAD3 genomes

AF:

0.0176

AC:

2673

AN:

152036

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0609

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00694

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000338

Gnomad OTH

AF:

0.0110

GnomAD3 exomes

AF:

0.00475

AC:

1160

AN:

244098

Hom.:

AF XY:

0.00345

AC XY:

458

AN XY:

132634

show subpopulations

Gnomad AFR exome

AF:

0.0642

Gnomad AMR exome

AF:

0.00275

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000263

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000223

Gnomad OTH exome

AF:

0.00199

GnomAD4 exome

AF:

0.00187

AC:

2713

AN:

1453356

Hom.:

Cov.:

AF XY:

0.00161

AC XY:

1163

AN XY:

723092

show subpopulations

Gnomad4 AFR exome

AF:

0.0650

Gnomad4 AMR exome

AF:

0.00284

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000197

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000134

Gnomad4 OTH exome

AF:

0.00390

GnomAD4 genome

AF:

0.0176

AC:

2680

AN:

152154

Hom.:

Cov.:

AF XY:

0.0171

AC XY:

1275

AN XY:

74394

show subpopulations

Gnomad4 AFR

AF:

0.0609

Gnomad4 AMR

AF:

0.00693

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000338

Gnomad4 OTH

AF:

0.0109

Alfa

AF:

0.00153

Hom.:

Bravo

AF:

0.0202

ESP6500AA

AF:

0.0611

AC:

269

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.00576

AC:

699

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.000218

EpiControl

AF:

0.000237

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10Other:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3Other:1

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Sep 04, 2015	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 21, 2020	This variant is associated with the following publications: (PMID: 26139345, 27884173, 10873396, 20981092) -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
not provided, no classification provided	literature only	Retina International	-	- -

Leber congenital amaurosis 4

Benign:2Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

not specified

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 18, 2022	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 21, 2014	- -

Retinitis pigmentosa;C1858386:Leber congenital amaurosis 4

Benign:1

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 05, 2022

- -

Retinitis Pigmentosa, Dominant

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Retinitis pigmentosa

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.064

BayesDel_addAF

Benign

-0.51

BayesDel_noAF

Benign

-0.45

CADD

Benign

0.025

DANN

Benign

0.29

DEOGEN2

Benign

0.020

T;.;T;.;.;.

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.0019

LIST_S2

Benign

0.71

T;T;T;T;T;T

MetaRNN

Benign

0.0032

T;T;T;T;T;T

MetaSVM

Benign

-0.78

MutationAssessor

Benign

0.34

N;.;.;.;.;.

MutationTaster

Benign

1.0

N;N;N;N;N;N;N

PrimateAI

Benign

0.26

PROVEAN

Benign

0.050

N;N;.;.;.;.

REVEL

Benign

0.13

Sift

Benign

0.15

T;T;.;.;.;.

Sift4G

Benign

0.15

T;T;T;T;T;T

Polyphen

0.0010

B;B;.;.;.;B

Vest4

0.13

MVP

0.88

MPC

0.19

ClinPred

0.0022

GERP RS

0.52

Varity_R

0.023

gMVP

0.29

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