rs16955851

Positions:

chr17-6428382-T-A

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 2P and 13B. PM1BP4_StrongBP6BS1BS2

The NM_014336.5(AIPL1):c.401A>T(p.Tyr134Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00578 in 1,612,788 control chromosomes in the GnomAD database, including 49 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 0.0039 ( 2 hom., cov: 33)

Exomes 𝑓: 0.0060 ( 47 hom. )

Consequence

AIPL1
NM_014336.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:8

Conservation

PhyloP100: 7.67

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 -11 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=0.024469882).

BP6

Variant 17-6428382-T-A is Benign according to our data. Variant chr17-6428382-T-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 196465.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=1, Benign=5}. Variant chr17-6428382-T-A is described in Lovd as [Pathogenic]. Variant chr17-6428382-T-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00395 (601/152328) while in subpopulation NFE AF= 0.00666 (453/68024). AF 95% confidence interval is 0.00615. There are 2 homozygotes in gnomad4. There are 272 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AIPL1	NM_014336.5 linkuse as main transcript	c.401A>T	p.Tyr134Phe	missense_variant	3/6	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.401A>T	p.Tyr134Phe	missense_variant	3/6	1	NM_014336.5	ENSP00000370521.3		Q9NZN9-1

Frequencies

GnomAD3 genomes

AF:

0.00395

AC:

601

AN:

152210

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000989

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00471

Gnomad ASJ

AF:

0.000865

Gnomad EAS

AF:

0.000386

Gnomad SAS

AF:

0.00248

Gnomad FIN

AF:

0.000941

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00666

Gnomad OTH

AF:

0.00382

GnomAD3 exomes

AF:

0.00401

AC:

1003

AN:

250268

Hom.:

AF XY:

0.00411

AC XY:

557

AN XY:

135384

show subpopulations

Gnomad AFR exome

AF:

0.00142

Gnomad AMR exome

AF:

0.00289

Gnomad ASJ exome

AF:

0.00149

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00281

Gnomad FIN exome

AF:

0.000682

Gnomad NFE exome

AF:

0.00647

Gnomad OTH exome

AF:

0.00490

GnomAD4 exome

AF:

0.00597

AC:

8720

AN:

1460460

Hom.:

Cov.:

AF XY:

0.00584

AC XY:

4243

AN XY:

726594

show subpopulations

Gnomad4 AFR exome

AF:

0.00116

Gnomad4 AMR exome

AF:

0.00329

Gnomad4 ASJ exome

AF:

0.00145

Gnomad4 EAS exome

AF:

0.0000756

Gnomad4 SAS exome

AF:

0.00364

Gnomad4 FIN exome

AF:

0.000961

Gnomad4 NFE exome

AF:

0.00705

Gnomad4 OTH exome

AF:

0.00457

GnomAD4 genome

AF:

0.00395

AC:

601

AN:

152328

Hom.:

Cov.:

AF XY:

0.00365

AC XY:

272

AN XY:

74492

show subpopulations

Gnomad4 AFR

AF:

0.000986

Gnomad4 AMR

AF:

0.00471

Gnomad4 ASJ

AF:

0.000865

Gnomad4 EAS

AF:

0.000386

Gnomad4 SAS

AF:

0.00248

Gnomad4 FIN

AF:

0.000941

Gnomad4 NFE

AF:

0.00666

Gnomad4 OTH

AF:

0.00378

Alfa

AF:

0.00567

Hom.:

Bravo

AF:

0.00402

TwinsUK

AF:

0.00836

AC:

ALSPAC

AF:

0.00934

AC:

ESP6500AA

AF:

0.00272

AC:

ESP6500EA

AF:

0.00686

AC:

ExAC

AF:

0.00418

AC:

508

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00589

EpiControl

AF:

0.00575

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:8

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Benign:4

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 04, 2019	The p.Tyr134Phe variant in AIPL1 is classified as benign because it has been identified in 0.7% (840/129112) of European chromosomes and 6 homozygotes by gnomAD (http://gnomad.broadinstitute.org). ACMG/AMP Criteria applied: BA1. -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 05, 2015	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 18, 2022	Variant summary: AIPL1 c.401A>T (p.Tyr134Phe) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.004 in 250268 control chromosomes in the gnomAD database, including 6 homozygotes. The observed variant frequency is approximately 3.58 fold of the estimated maximal expected allele frequency for a pathogenic variant in AIPL1 causing Leber Congenital Amaurosis phenotype (0.0011), strongly suggesting that the variant is benign. c.401A>T has been reported in the literature in individuals affected with Leber Congenital Amaurosis and in ethnically-matched controls (Astuti_2016). Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments: four classify as likely benign/benign while two classify as VUS. Based on the evidence outlined above, the variant was classified as benign. -

Leber congenital amaurosis 4

Uncertain:1Benign:1

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Uncertain significance, 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. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 09, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2024	AIPL1: BS2 -

Leber congenital amaurosis 1

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.029

BayesDel_noAF

Pathogenic

0.20

CADD

Uncertain

DANN

Uncertain

0.98

DEOGEN2

Benign

0.37

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

Eigen

Uncertain

0.54

Eigen_PC

Uncertain

0.55

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.76

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

M_CAP

Benign

0.054

MetaRNN

Benign

0.024

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

MetaSVM

Uncertain

0.45

MutationAssessor

Uncertain

2.5

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

PrimateAI

Uncertain

0.68

PROVEAN

Uncertain

-2.4

N;.;.;.;.;.;.;.

REVEL

Pathogenic

0.84

Sift

Benign

0.12

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

Sift4G

Benign

0.15

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

Polyphen

0.66

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

Vest4

0.71

MVP

0.90

MPC

0.52

ClinPred

0.019

GERP RS

4.9

Varity_R

0.65

gMVP

0.60

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