17-6426748-T-C

Variant names:

• chr17-6426748-T-C
• rs2292546
• NM_014336.5:c.651A>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.651A>G​(p.Pro217Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.737 in 1,613,650 control chromosomes in the GnomAD database, including 439,818 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★). Synonymous variant affecting the same amino acid position (i.e. P217P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.73 (41112 hom., cov: 33)
  • Exomes 𝑓: 0.74 (398706 hom.)
• Consequence: AIPL1 NM_014336.5 synonymous
• Clinical Significance: Benign reviewed by expert panel B:12 O:1
• Conservation: PhyloP100: -2.52
• 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=-0.83).
• BP6: Variant 17-6426748-T-C is Benign according to our data. Variant chr17-6426748-T-C is described in ClinVar as Benign. ClinVar VariationId is 99805.Status of the report is reviewed_by_expert_panel, 3 stars.
• BP7: Synonymous conserved (PhyloP=-2.52 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.746 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.651A>G	p.Pro217Pro	synonymous	Exon 5 of 6	NP_055151.3
	AIPL1	NM_001285399.3		c.615A>G	p.Pro205Pro	synonymous	Exon 5 of 6	NP_001272328.1	Q7Z3H1
	AIPL1	NM_001285400.3		c.585A>G	p.Pro195Pro	synonymous	Exon 5 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.651A>G	p.Pro217Pro	synonymous	Exon 5 of 6	ENSP00000370521.3	Q9NZN9-1
	AIPL1	ENST00000574506.5	TSL:1	c.615A>G	p.Pro205Pro	synonymous	Exon 5 of 6	ENSP00000458456.1	Q7Z3H1
	AIPL1	ENST00000570466.5	TSL:1	c.585A>G	p.Pro195Pro	synonymous	Exon 5 of 6	ENSP00000461287.1	Q9NZN9-4

Frequencies

GnomAD3 genomes AF: 0.734 AC: 111557 AN: 152020 Hom.: 41079 Cov.: 33

Gnomad AFR AF: 0.727

Gnomad AMI AF: 0.659

Gnomad AMR AF: 0.741

Gnomad ASJ AF: 0.828

Gnomad EAS AF: 0.672

Gnomad SAS AF: 0.665

Gnomad FIN AF: 0.662

Gnomad MID AF: 0.880

Gnomad NFE AF: 0.751

Gnomad OTH AF: 0.772

GnomAD2 exomes AF: 0.728 AC: 182942 AN: 251182 AF XY: 0.727

Gnomad AFR exome AF: 0.724

Gnomad AMR exome AF: 0.753

Gnomad ASJ exome AF: 0.831

Gnomad EAS exome AF: 0.674

Gnomad FIN exome AF: 0.660

Gnomad NFE exome AF: 0.748

Gnomad OTH exome AF: 0.756

GnomAD4 exome AF: 0.738 AC: 1077902 AN: 1461512 Hom.: 398706 Cov.: 66 AF XY: 0.736 AC XY: 535310 AN XY: 727068

African (AFR) AF: 0.726 AC: 24293 AN: 33480

American (AMR) AF: 0.750 AC: 33532 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.834 AC: 21783 AN: 26130

East Asian (EAS) AF: 0.664 AC: 26344 AN: 39700

South Asian (SAS) AF: 0.680 AC: 58619 AN: 86258

European-Finnish (FIN) AF: 0.660 AC: 35064 AN: 53128

Middle Eastern (MID) AF: 0.868 AC: 5009 AN: 5768

European-Non Finnish (NFE) AF: 0.745 AC: 828121 AN: 1111938

Other (OTH) AF: 0.747 AC: 45137 AN: 60386

GnomAD4 genome AF: 0.734 AC: 111649 AN: 152138 Hom.: 41112 Cov.: 33 AF XY: 0.728 AC XY: 54123 AN XY: 74376

African (AFR) AF: 0.728 AC: 30205 AN: 41506

American (AMR) AF: 0.741 AC: 11328 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.828 AC: 2874 AN: 3472

East Asian (EAS) AF: 0.670 AC: 3451 AN: 5148

South Asian (SAS) AF: 0.665 AC: 3208 AN: 4822

European-Finnish (FIN) AF: 0.662 AC: 7013 AN: 10592

Middle Eastern (MID) AF: 0.884 AC: 260 AN: 294

European-Non Finnish (NFE) AF: 0.751 AC: 51080 AN: 67984

Other (OTH) AF: 0.770 AC: 1630 AN: 2116

Alfa AF: 0.748 Hom.: 166950

Bravo AF: 0.741

Asia WGS AF: 0.661 AC: 2298 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	not provided (4)
-	-	2	Leber congenital amaurosis 4 (2)
-	-	1	AIPL1-related retinopathy (1)
-	-	1	Retinitis pigmentosa (1)
-	-	1	Retinitis Pigmentosa, Dominant (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	5.0
DANN	Benign	0.51
PhyloP100		-2.5
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs2292546; hg19: chr17-6330068; COSMIC: COSV51506460; COSMIC: COSV51506460;