NM_014336.5:c.466-26T>C

Variant names:

• chr17-6427083-A-G
• rs925615
• NM_014336.5:c.466-26T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_014336.5(AIPL1):​c.466-26T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0764 in 1,613,450 control chromosomes in the GnomAD database, including 4,977 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.065 (358 hom., cov: 32)
  • Exomes 𝑓: 0.078 (4619 hom.)
• Consequence: AIPL1 NM_014336.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.140
• Publications: 5 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 -20 ACMG points.

• BP4: This position, referring to a specific DNA site, is a probable branch point but rather VUS (scored 4 / 10). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 17-6427083-A-G is Benign according to our data. Variant chr17-6427083-A-G is described in ClinVar as Benign. ClinVar VariationId is 1245637.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0825 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AIPL1	NM_014336.5	c.466-26T>C		intron_variant	Intron 3 of 5	ENST00000381129.8	NP_055151.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AIPL1	ENST00000381129.8	c.466-26T>C		intron_variant	Intron 3 of 5	1	NM_014336.5	ENSP00000370521.3

Frequencies

GnomAD3 genomes AF: 0.0652 AC: 9917 AN: 152112 Hom.: 358 Cov.: 32

Gnomad AFR AF: 0.0573

Gnomad AMI AF: 0.0746

Gnomad AMR AF: 0.0380

Gnomad ASJ AF: 0.0550

Gnomad EAS AF: 0.0892

Gnomad SAS AF: 0.0550

Gnomad FIN AF: 0.0425

Gnomad MID AF: 0.0759

Gnomad NFE AF: 0.0791

Gnomad OTH AF: 0.0580

GnomAD2 exomes AF: 0.0628 AC: 15760 AN: 250826 AF XY: 0.0638

Gnomad AFR exome AF: 0.0541

Gnomad AMR exome AF: 0.0272

Gnomad ASJ exome AF: 0.0546

Gnomad EAS exome AF: 0.0858

Gnomad FIN exome AF: 0.0398

Gnomad NFE exome AF: 0.0778

Gnomad OTH exome AF: 0.0658

GnomAD4 exome AF: 0.0775 AC: 113274 AN: 1461220 Hom.: 4619 Cov.: 36 AF XY: 0.0767 AC XY: 55784 AN XY: 726908

African (AFR) AF: 0.0566 AC: 1893 AN: 33472

American (AMR) AF: 0.0285 AC: 1274 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0559 AC: 1462 AN: 26136

East Asian (EAS) AF: 0.0760 AC: 3015 AN: 39696

South Asian (SAS) AF: 0.0569 AC: 4906 AN: 86244

European-Finnish (FIN) AF: 0.0430 AC: 2282 AN: 53094

Middle Eastern (MID) AF: 0.0680 AC: 383 AN: 5636

European-Non Finnish (NFE) AF: 0.0840 AC: 93432 AN: 1111848

Other (OTH) AF: 0.0766 AC: 4627 AN: 60374

GnomAD4 genome AF: 0.0652 AC: 9922 AN: 152230 Hom.: 358 Cov.: 32 AF XY: 0.0635 AC XY: 4729 AN XY: 74430

African (AFR) AF: 0.0573 AC: 2380 AN: 41534

American (AMR) AF: 0.0380 AC: 581 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0550 AC: 191 AN: 3472

East Asian (EAS) AF: 0.0892 AC: 461 AN: 5168

South Asian (SAS) AF: 0.0552 AC: 266 AN: 4816

European-Finnish (FIN) AF: 0.0425 AC: 451 AN: 10620

Middle Eastern (MID) AF: 0.0782 AC: 23 AN: 294

European-Non Finnish (NFE) AF: 0.0791 AC: 5380 AN: 68006

Other (OTH) AF: 0.0573 AC: 121 AN: 2110

Alfa AF: 0.0687 Hom.: 131

Bravo AF: 0.0644

Asia WGS AF: 0.0740 AC: 258 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	8.0
DANN	Benign	0.80
PhyloP100		-0.14
BranchPoint Hunter		4.0
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs925615; hg19: chr17-6330403;