rs12453262

Positions:

• chr17-6428516-T-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_014336.5(AIPL1):​c.277-10A>C variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.56 in 1,611,246 control chromosomes in the GnomAD database, including 256,149 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.53 (21911 hom., cov: 34)
  • Exomes 𝑓: 0.56 (234238 hom.)
• Consequence: AIPL1 NM_014336.5 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00001746
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8 O:1
• Conservation: PhyloP100: -0.0900

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 17-6428516-T-G is Benign according to our data. Variant chr17-6428516-T-G is described in ClinVar as [Likely_benign]. Clinvar id is 99796.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-6428516-T-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.601 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AIPL1	NM_014336.5	c.277-10A>C		splice_polypyrimidine_tract_variant, intron_variant		ENST00000381129.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AIPL1	ENST00000381129.8	c.277-10A>C		splice_polypyrimidine_tract_variant, intron_variant		1	NM_014336.5	P1

Frequencies

GnomAD3 genomes AF: 0.527 AC: 80055 AN: 151996 Hom.: 21901 Cov.: 34

Gnomad AFR AF: 0.383

Gnomad AMI AF: 0.462

Gnomad AMR AF: 0.611

Gnomad ASJ AF: 0.716

Gnomad EAS AF: 0.497

Gnomad SAS AF: 0.516

Gnomad FIN AF: 0.551

Gnomad MID AF: 0.747

Gnomad NFE AF: 0.583

Gnomad OTH AF: 0.590

GnomAD3 exomes AF: 0.566 AC: 141360 AN: 249608 Hom.: 40894 AF XY: 0.567 AC XY: 76548 AN XY: 135058

Gnomad AFR exome AF: 0.377

Gnomad AMR exome AF: 0.656

Gnomad ASJ exome AF: 0.720

Gnomad EAS exome AF: 0.504

Gnomad SAS exome AF: 0.518

Gnomad FIN exome AF: 0.552

Gnomad NFE exome AF: 0.577

Gnomad OTH exome AF: 0.600

GnomAD4 exome AF: 0.564 AC: 822435 AN: 1459132 Hom.: 234238 Cov.: 44 AF XY: 0.563 AC XY: 409098 AN XY: 726038

Gnomad4 AFR exome AF: 0.377

Gnomad4 AMR exome AF: 0.649

Gnomad4 ASJ exome AF: 0.722

Gnomad4 EAS exome AF: 0.497

Gnomad4 SAS exome AF: 0.522

Gnomad4 FIN exome AF: 0.549

Gnomad4 NFE exome AF: 0.567

Gnomad4 OTH exome AF: 0.573

GnomAD4 genome AF: 0.527 AC: 80107 AN: 152114 Hom.: 21911 Cov.: 34 AF XY: 0.525 AC XY: 39051 AN XY: 74330

Gnomad4 AFR AF: 0.384

Gnomad4 AMR AF: 0.611

Gnomad4 ASJ AF: 0.716

Gnomad4 EAS AF: 0.496

Gnomad4 SAS AF: 0.516

Gnomad4 FIN AF: 0.551

Gnomad4 NFE AF: 0.583

Gnomad4 OTH AF: 0.589

Alfa AF: 0.585 Hom.: 36336

Bravo AF: 0.526

Asia WGS AF: 0.486 AC: 1691 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 20, 2015	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Leber congenital amaurosis 4 Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

not provided Benign:1 Other:1

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
not provided, no classification provided	literature only	Retina International	-	- -

Retinitis Pigmentosa, Recessive Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Retinitis pigmentosa;C1858386:Leber congenital amaurosis 4 Benign:1

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Aug 11, 2021

- -

Retinitis pigmentosa Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	2.5
DANN	Benign	0.69

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000017
dbscSNV1_RF	Benign	0.0020
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: rs12453262; hg19: chr17-6331836; COSMIC: COSV51506213;