rs62637015

chr17-6425710-C-Achr17-6425710-C-T

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 2P and 13B. PM5 BP4_Strong BP6 BS1 BS2

The NM_014336.5(AIPL1):c.905G>T(p.Arg302Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00155 in 1,608,168 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R302H) has been classified as Pathogenic.

• Frequency:
  • Genomes: 𝑓 0.0013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0016 (11 hom.)
• Consequence: AIPL1 NM_014336.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:9 O:2
• Conservation: PhyloP100: -0.221

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]

ACMG classification

Verdict is Benign. Variant got -11 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-6425710-C-T is described in Lovd as [Pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.0067735612).
• BP6: Variant 17-6425710-C-A is Benign according to our data. Variant chr17-6425710-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 65712.We mark this variant Likely_benign, oryginal submissions are: {Benign=3, not_provided=2, Likely_benign=3, Uncertain_significance=1}. Variant chr17-6425710-C-A is described in Lovd as [Likely_benign]. Variant chr17-6425710-C-A is described in Lovd as [Benign]. Variant chr17-6425710-C-A is described in Lovd as [Pathogenic].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00125 (191/152308) while in subpopulation SAS AF= 0.0085 (41/4822). AF 95% confidence interval is 0.00644. There are 0 homozygotes in gnomad4. There are 100 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome at 3 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AIPL1	NM_014336.5	c.905G>T	p.Arg302Leu	missense_variant	6/6	ENST00000381129.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AIPL1	ENST00000381129.8	c.905G>T	p.Arg302Leu	missense_variant	6/6	1	NM_014336.5	P1

Frequencies

GnomAD3 genomes AF: 0.00125 AC: 190 AN: 152190 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00308

Gnomad ASJ AF: 0.00461

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00829

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00100

Gnomad OTH AF: 0.00525

GnomAD3 exomes AF: 0.00261 AC: 639 AN: 244746 Hom.: 3 AF XY: 0.00296 AC XY: 394 AN XY: 132942

Gnomad AFR exome AF: 0.0000617

Gnomad AMR exome AF: 0.00405

Gnomad ASJ exome AF: 0.00507

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00885

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00133

Gnomad OTH exome AF: 0.00461

GnomAD4 exome AF: 0.00158 AC: 2305 AN: 1455860 Hom.: 11 Cov.: 31 AF XY: 0.00185 AC XY: 1338 AN XY: 724624

Gnomad4 AFR exome AF: 0.000149

Gnomad4 AMR exome AF: 0.00403

Gnomad4 ASJ exome AF: 0.00574

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00936

Gnomad4 FIN exome AF: 0.0000211

Gnomad4 NFE exome AF: 0.000860

Gnomad4 OTH exome AF: 0.00253

GnomAD4 genome AF: 0.00125 AC: 191 AN: 152308 Hom.: 0 Cov.: 32 AF XY: 0.00134 AC XY: 100 AN XY: 74480

Gnomad4 AFR AF: 0.000168

Gnomad4 AMR AF: 0.00307

Gnomad4 ASJ AF: 0.00461

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00850

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00100

Gnomad4 OTH AF: 0.00520

Alfa AF: 0.00143 Hom.: 2

Bravo AF: 0.00159

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000814 AC: 7

ExAC AF: 0.00261 AC: 317

Asia WGS AF: 0.00346 AC: 12 AN: 3478

EpiCase AF: 0.00207

EpiControl AF: 0.00237

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:9 Other:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:5 Other:1

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 16, 2019	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2023	AIPL1: BP4, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
not provided, no classification provided	literature only	Retina International	-	- -

Leber congenital amaurosis 4 Uncertain:1 Benign:1 Other:1

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 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, 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. -
not provided, no classification provided	literature only	GeneReviews	-	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Nov 20, 2014

- -

Leber congenital amaurosis 1 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

AIPL1-related condition Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 12, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.16
Cadd	Benign	14
Dann	Benign	0.96
DEOGEN2	Benign	0.26	T;.;T;.;.;.
Eigen	Benign	-0.94
Eigen_PC	Benign	-0.91
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.34	T;T;T;T;T;T
M_CAP	Benign	0.039	D
MetaRNN	Benign	0.0068	T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.55	N;.;.;.;.;.
MutationTaster	Benign	1.0	D;N;N;N;N;N;N
PrimateAI	Benign	0.29	T
PROVEAN	Uncertain	-3.4	D;D;.;.;.;.
REVEL	Uncertain	0.41
Sift	Benign	0.21	T;T;.;.;.;.
Sift4G	Benign	0.25	T;T;T;T;T;T
Polyphen		0.0030	B;B;.;.;.;B
Vest4		0.086
MVP		0.43
MPC		0.23
ClinPred		0.063	T
GERP RS		-3.9
Varity_R		0.20
gMVP		0.43

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

Other links and lift over

dbSNP: rs62637015; hg19: chr17-6329030; COSMIC: COSV51508130; COSMIC: COSV51508130;