rs62653020

Positions:

• chr17-6433928-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The ENST00000381129.8(AIPL1):​c.267C>T​(p.Cys89=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00493 in 1,613,722 control chromosomes in the GnomAD database, including 31 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 0.0035 (2 hom., cov: 30)
  • Exomes 𝑓: 0.0051 (29 hom.)
• Consequence: AIPL1 ENST00000381129.8 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:6 O:1
• Conservation: PhyloP100: -0.523

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.71).
• BP6: Variant 17-6433928-G-A is Benign according to our data. Variant chr17-6433928-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 95582.We mark this variant Likely_benign, oryginal submissions are: {Benign=3, Likely_benign=1, Uncertain_significance=3, not_provided=1}. Variant chr17-6433928-G-A is described in Lovd as [Benign]. Variant chr17-6433928-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-0.523 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00355 (540/152258) while in subpopulation NFE AF= 0.0052 (354/68028). AF 95% confidence interval is 0.00476. There are 2 homozygotes in gnomad4. There are 229 alleles in male gnomad4 subpopulation. Median coverage is 30. 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	c.267C>T	p.Cys89=	synonymous_variant	2/6	ENST00000381129.8	NP_055151.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AIPL1	ENST00000381129.8	c.267C>T	p.Cys89=	synonymous_variant	2/6	1	NM_014336.5	ENSP00000370521	P1

Frequencies

GnomAD3 genomes AF: 0.00356 AC: 541 AN: 152140 Hom.: 2 Cov.: 30

Gnomad AFR AF: 0.00109

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00183

Gnomad ASJ AF: 0.0153

Gnomad EAS AF: 0.000774

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00452

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00522

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00417 AC: 1043 AN: 250336 Hom.: 5 AF XY: 0.00407 AC XY: 551 AN XY: 135320

Gnomad AFR exome AF: 0.000618

Gnomad AMR exome AF: 0.00171

Gnomad ASJ exome AF: 0.0129

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.000918

Gnomad FIN exome AF: 0.00559

Gnomad NFE exome AF: 0.00595

Gnomad OTH exome AF: 0.00344

GnomAD4 exome AF: 0.00508 AC: 7422 AN: 1461464 Hom.: 29 Cov.: 33 AF XY: 0.00500 AC XY: 3634 AN XY: 726972

Gnomad4 AFR exome AF: 0.000628

Gnomad4 AMR exome AF: 0.00166

Gnomad4 ASJ exome AF: 0.0128

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.000812

Gnomad4 FIN exome AF: 0.00569

Gnomad4 NFE exome AF: 0.00565

Gnomad4 OTH exome AF: 0.00537

GnomAD4 genome AF: 0.00355 AC: 540 AN: 152258 Hom.: 2 Cov.: 30 AF XY: 0.00308 AC XY: 229 AN XY: 74434

Gnomad4 AFR AF: 0.00108

Gnomad4 AMR AF: 0.00183

Gnomad4 ASJ AF: 0.0153

Gnomad4 EAS AF: 0.000776

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00452

Gnomad4 NFE AF: 0.00520

Gnomad4 OTH AF: 0.00236

Alfa AF: 0.00590 Hom.: 0

Bravo AF: 0.00342

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00491

EpiControl AF: 0.00428

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:6 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:3 Other:1

not provided, no classification provided	literature only	Retina International	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	AIPL1: BP4, BP7, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Aug 15, 2023	- -

Leber congenital amaurosis 4 Uncertain:1 Benign: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	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, 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 specified Benign:2

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 19, 2016	- -

Retinitis Pigmentosa, Recessive Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Retinal dystrophy Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg

Jan 01, 2012

- -

Retinitis Pigmentosa, Dominant Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
CADD	Benign	1.6
DANN	Benign	0.68

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: rs62653020; hg19: chr17-6337248;