rs200899521

Positions:

chr17-6434083-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PP3_Strong

The NM_014336.5(AIPL1):c.112C>T(p.Arg38Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000273 in 1,613,698 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R38H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 30)

Exomes 𝑓: 0.000027 ( 1 hom. )

Consequence

AIPL1
NM_014336.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 9.60

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 Uncertain_significance. Variant got 4 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.946

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AIPL1	NM_014336.5 linkuse as main transcript	c.112C>T	p.Arg38Cys	missense_variant	2/6	ENST00000381129.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AIPL1	ENST00000381129.8 linkuse as main transcript	c.112C>T	p.Arg38Cys	missense_variant	2/6	1	NM_014336.5	P1	Q9NZN9-1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152010

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000398

AC:

AN:

250994

Hom.:

AF XY:

0.0000369

AC XY:

AN XY:

135666

show subpopulations

Gnomad AFR exome

AF:

0.0000616

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000982

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000274

AC:

AN:

1461688

Hom.:

Cov.:

AF XY:

0.0000303

AC XY:

AN XY:

727132

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.000201

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000696

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000189

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152010

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74240

show subpopulations

Gnomad4 AFR

AF:

0.0000242

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.00160

Hom.:

Bravo

AF:

0.0000416

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ExAC

AF:

0.0000330

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Sep 22, 2016	- -
Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The AIPL1 p.Arg38Cys variant was identified in the literature in 1 of 1284 proband chromosomes (frequency: 0.0008) from individuals with Leber congenital amaurosis (Stone_2007_PMID:17964524). The variant was identified in dbSNP (ID: rs200899521) and ClinVar (classified as uncertain significance by the Center for Pediatric Genomic Medicine Children's Mercy Hospital and Clinics). The variant was identified in control databases in 11 of 282324 chromosomes (1 homozygous) at a frequency of 0.00003896 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: Latino in 4 of 35398 chromosomes (freq: 0.000113), South Asian in 3 of 30550 chromosomes (freq: 0.000098), African in 1 of 24916 chromosomes (freq: 0.00004) and European (non-Finnish) in 3 of 128980 chromosomes (freq: 0.000023), but was not observed in the Ashkenazi Jewish, East Asian, European (Finnish), or Other populations. The p.Arg38 residue is conserved in mammals but not in more distantly related organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. Data from two functional studies demonstrated that the chaperone ability of the AIPL1 protein containing the p.R38C variant did not differ significantly from the wild type (Gopalakrishna_2016_PMID:27268253), and the p.R38C variant did not significantly affect the binding of farnesyl-Cys-AMCA to AIPL1 (Majumder_2013_PMID:23737531). In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Aug 10, 2023

Variant summary: AIPL1 c.112C>T (p.Arg38Cys) results in a non-conservative amino acid change located in the FKBP-type peptidyl-prolyl cis-trans isomerase domain (IPR001179) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-05 in 250994 control chromosomes in the gnomAD database, including 1 homozygote. This frequency is not significantly higher than estimated for a pathogenic variant in AIPL1 causing Leber Congenital Amaurosis (4e-05 vs 0.0011), allowing no conclusion about variant significance. c.112C>T has been reported in the literature in individuals affected with Leber Congenital Amaurosis or nonsyndromic blindness without strong evidence of causality (Stone_2007, Dineiro_2020). These reports do not provide unequivocal conclusions about association of the variant with Leber Congenital Amaurosis. Publications reports experimental evidence evaluating an impact on protein function, finding no effect of the variant on the ability for AIPL1 to interact with FAT10 or to chaperone PDE6C (Boehm_2020, Gopalakrishna_2016). The following publications have been ascertained in the context of this evaluation (PMID: 17964524, 32483926, 32817338, 27268253). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Both submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Leber congenital amaurosis 4

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Feb 09, 2022

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 38 of the AIPL1 protein (p.Arg38Cys). This variant is present in population databases (rs200899521, gnomAD 0.01%), including at least one homozygous and/or hemizygous individual. This missense change has been observed in individual(s) with clinical features of Leber congenital amaurosis (PMID: 17964524). ClinVar contains an entry for this variant (Variation ID: 377207). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). Experimental studies have shown that this missense change does not substantially affect AIPL1 function (PMID: 23737531, 27268253). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Pathogenic

0.27

BayesDel_noAF

Pathogenic

0.37

CADD

Pathogenic

DANN

Benign

0.97

DEOGEN2

Benign

0.39

T;.;.;.;T;T

Eigen

Pathogenic

0.77

Eigen_PC

Pathogenic

0.72

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.93

D;D;D;D;D;D

M_CAP

Uncertain

0.21

MetaRNN

Pathogenic

0.95

D;D;D;D;D;D

MetaSVM

Uncertain

0.68

MutationAssessor

Uncertain

2.2

M;M;.;M;.;.

MutationTaster

Benign

1.0

D;D;D;D;D;D;D;D

PrimateAI

Benign

0.38

PROVEAN

Pathogenic

-5.8

D;D;.;.;.;.

REVEL

Pathogenic

0.93

Sift

Benign

0.035

D;D;.;.;.;.

Sift4G

Pathogenic

0.0010

D;D;D;D;D;.

Polyphen

1.0

D;D;D;.;.;.

Vest4

0.83

MutPred

0.84

Gain of catalytic residue at K41 (P = 0.0519);Gain of catalytic residue at K41 (P = 0.0519);Gain of catalytic residue at K41 (P = 0.0519);Gain of catalytic residue at K41 (P = 0.0519);Gain of catalytic residue at K41 (P = 0.0519);Gain of catalytic residue at K41 (P = 0.0519);

MVP

0.97

MPC

0.87

ClinPred

0.82

GERP RS

4.8

Varity_R

0.58

gMVP

0.84

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.080

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