17-6428483-T-C

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -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:10
• Conservation: PhyloP100: -0.306
• Publications: 24 publications found

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 Gene-Disease associations (from GenCC):

• AIPL1-related retinopathy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• Leber congenital amaurosis 4

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• Leber congenital amaurosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId is 166655.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014336.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AIPL1	NM_014336.5	MANE Select	c.300A>G	p.Leu100Leu	synonymous	Exon 3 of 6	NP_055151.3
	AIPL1	NM_001285399.3		c.264A>G	p.Leu88Leu	synonymous	Exon 3 of 6	NP_001272328.1	Q7Z3H1
	AIPL1	NM_001285400.3		c.234A>G	p.Leu78Leu	synonymous	Exon 3 of 6	NP_001272329.1	Q9NZN9-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AIPL1	ENST00000381129.8	TSL:1 MANE Select	c.300A>G	p.Leu100Leu	synonymous	Exon 3 of 6	ENSP00000370521.3	Q9NZN9-1
	AIPL1	ENST00000574506.5	TSL:1	c.264A>G	p.Leu88Leu	synonymous	Exon 3 of 6	ENSP00000458456.1	Q7Z3H1
	AIPL1	ENST00000570466.5	TSL:1	c.234A>G	p.Leu78Leu	synonymous	Exon 3 of 6	ENSP00000461287.1	Q9NZN9-4

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

GnomAD2 exomes AF: 0.643 AC: 161264 AN: 250792 AF XY: 0.644

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 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

African (AFR) AF: 0.491 AC: 16415 AN: 33462

American (AMR) AF: 0.702 AC: 31412 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.770 AC: 20128 AN: 26134

East Asian (EAS) AF: 0.546 AC: 21657 AN: 39698

South Asian (SAS) AF: 0.618 AC: 53294 AN: 86252

European-Finnish (FIN) AF: 0.616 AC: 32723 AN: 53122

Middle Eastern (MID) AF: 0.778 AC: 4488 AN: 5768

European-Non Finnish (NFE) AF: 0.652 AC: 724881 AN: 1111732

Other (OTH) AF: 0.648 AC: 39101 AN: 60384

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

African (AFR) AF: 0.495 AC: 20566 AN: 41526

American (AMR) AF: 0.664 AC: 10154 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.766 AC: 2658 AN: 3470

East Asian (EAS) AF: 0.542 AC: 2789 AN: 5144

South Asian (SAS) AF: 0.605 AC: 2920 AN: 4826

European-Finnish (FIN) AF: 0.618 AC: 6561 AN: 10614

Middle Eastern (MID) AF: 0.793 AC: 233 AN: 294

European-Non Finnish (NFE) AF: 0.664 AC: 45117 AN: 67996

Other (OTH) AF: 0.654 AC: 1382 AN: 2114

Alfa AF: 0.650 Hom.: 87461

Bravo AF: 0.611

Asia WGS AF: 0.550 AC: 1913 AN: 3478

EpiCase AF: 0.678

EpiControl AF: 0.683

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	3	not specified (3)
-	-	2	Leber congenital amaurosis 4 (2)
-	-	1	Retinitis pigmentosa (1)
-	-	1	Retinitis Pigmentosa, Recessive (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
CADD	Benign	6.2
DANN	Benign	0.66
PhyloP100		-0.31
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

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