17-6428483-T-C

Variant names:

• chr17-6428483-T-C
• rs8075035
• NM_014336.5:c.300A>G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_014336.5(AIPL1):​c.300A>G​(p.Leu100Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.643 in 1,613,462 control chromosomes in the GnomAD database, including 335,818 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.61 (28856 hom., cov: 34)
  • Exomes 𝑓: 0.65 (306962 hom.)
• Consequence: AIPL1 NM_014336.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.306

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.56).
• BP6: Variant 17-6428483-T-C is Benign according to our data. Variant chr17-6428483-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 166655.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-6428483-T-C is described in Lovd as [Benign]. Variant chr17-6428483-T-C is described in Lovd as [Likely_pathogenic]. Variant chr17-6428483-T-C is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-0.306 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.658 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AIPL1	NM_014336.5	c.300A>G	p.Leu100Leu	synonymous_variant	Exon 3 of 6	ENST00000381129.8	NP_055151.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AIPL1	ENST00000381129.8	c.300A>G	p.Leu100Leu	synonymous_variant	Exon 3 of 6	1	NM_014336.5	ENSP00000370521.3

Frequencies

GnomAD3 genomes AF: 0.610 AC: 92833 AN: 152074 Hom.: 28841 Cov.: 34

Gnomad AFR AF: 0.495

Gnomad AMI AF: 0.576

Gnomad AMR AF: 0.663

Gnomad ASJ AF: 0.766

Gnomad EAS AF: 0.544

Gnomad SAS AF: 0.605

Gnomad FIN AF: 0.618

Gnomad MID AF: 0.791

Gnomad NFE AF: 0.663

Gnomad OTH AF: 0.656

GnomAD3 exomes AF: 0.643 AC: 161264 AN: 250792 Hom.: 52550 AF XY: 0.644 AC XY: 87368 AN XY: 135604

Gnomad AFR exome AF: 0.489

Gnomad AMR exome AF: 0.708

Gnomad ASJ exome AF: 0.769

Gnomad EAS exome AF: 0.548

Gnomad SAS exome AF: 0.610

Gnomad FIN exome AF: 0.619

Gnomad NFE exome AF: 0.661

Gnomad OTH exome AF: 0.673

GnomAD4 exome AF: 0.646 AC: 944099 AN: 1461270 Hom.: 306962 Cov.: 64 AF XY: 0.646 AC XY: 469961 AN XY: 726968

Gnomad4 AFR exome AF: 0.491

Gnomad4 AMR exome AF: 0.702

Gnomad4 ASJ exome AF: 0.770

Gnomad4 EAS exome AF: 0.546

Gnomad4 SAS exome AF: 0.618

Gnomad4 FIN exome AF: 0.616

Gnomad4 NFE exome AF: 0.652

Gnomad4 OTH exome AF: 0.648

GnomAD4 genome AF: 0.610 AC: 92904 AN: 152192 Hom.: 28856 Cov.: 34 AF XY: 0.607 AC XY: 45177 AN XY: 74406

Gnomad4 AFR AF: 0.495

Gnomad4 AMR AF: 0.664

Gnomad4 ASJ AF: 0.766

Gnomad4 EAS AF: 0.542

Gnomad4 SAS AF: 0.605

Gnomad4 FIN AF: 0.618

Gnomad4 NFE AF: 0.664

Gnomad4 OTH AF: 0.654

Alfa AF: 0.661 Hom.: 67111

Bravo AF: 0.611

Asia WGS AF: 0.550 AC: 1913 AN: 3478

EpiCase AF: 0.678

EpiControl AF: 0.683

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 29, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:2

Jan 20, 2015

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Leber congenital amaurosis 4 Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Retinitis Pigmentosa, Recessive Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Retinitis pigmentosa Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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	-0.56
CADD	Benign	6.2
DANN	Benign	0.66

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: rs8075035; hg19: chr17-6331803; COSMIC: COSV51506018;