17-6423892-C-T

Variant names:

• chr17-6423892-C-T
• rs11869066
• NM_014336.5:c.*1568G>A

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.*1568G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0585 in 152,350 control chromosomes in the GnomAD database, including 313 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.059 (313 hom., cov: 33)
  • Exomes 𝑓: 0.059 (0 hom.)
• Consequence: AIPL1 NM_014336.5 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -2.58
• Publications: 4 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: G2P, Labcorp Genetics (formerly Invitae)
• Leber congenital amaurosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 17-6423892-C-T is Benign according to our data. Variant chr17-6423892-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 324569.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0792 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.*1568G>A		3_prime_UTR	Exon 6 of 6	NP_055151.3
	AIPL1	NM_001285399.3		c.*1568G>A		3_prime_UTR	Exon 6 of 6	NP_001272328.1	Q7Z3H1
	AIPL1	NM_001285400.3		c.*1568G>A		3_prime_UTR	Exon 6 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.*1568G>A		3_prime_UTR	Exon 6 of 6	ENSP00000370521.3	Q9NZN9-1
	AIPL1	ENST00000250087.9	TSL:1	c.*1568G>A		3_prime_UTR	Exon 5 of 5	ENSP00000250087.5	Q9NZN9-3
	AIPL1	ENST00000381128.2	TSL:1	n.*2595G>A		non_coding_transcript_exon	Exon 6 of 6	ENSP00000370520.2	J3KPI5

Frequencies

GnomAD3 genomes AF: 0.0585 AC: 8906 AN: 152198 Hom.: 312 Cov.: 33

Gnomad AFR AF: 0.0815

Gnomad AMI AF: 0.0603

Gnomad AMR AF: 0.0275

Gnomad ASJ AF: 0.0395

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0346

Gnomad FIN AF: 0.0582

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0591

Gnomad OTH AF: 0.0487

GnomAD4 exome AF: 0.0588 AC: 2 AN: 34 Hom.: 0 Cov.: 0 AF XY: 0.0455 AC XY: 1 AN XY: 22

African (AFR) AC: 0 AN: 0

American (AMR) AF: 0.00 AC: 0 AN: 2

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.125 AC: 1 AN: 8

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 22

Other (OTH) AF: 0.500 AC: 1 AN: 2

GnomAD4 genome AF: 0.0585 AC: 8916 AN: 152316 Hom.: 313 Cov.: 33 AF XY: 0.0571 AC XY: 4250 AN XY: 74480

African (AFR) AF: 0.0815 AC: 3389 AN: 41580

American (AMR) AF: 0.0274 AC: 420 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.0395 AC: 137 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5182

South Asian (SAS) AF: 0.0346 AC: 167 AN: 4824

European-Finnish (FIN) AF: 0.0582 AC: 617 AN: 10604

Middle Eastern (MID) AF: 0.0306 AC: 9 AN: 294

European-Non Finnish (NFE) AF: 0.0591 AC: 4019 AN: 68024

Other (OTH) AF: 0.0482 AC: 102 AN: 2116

Alfa AF: 0.0559 Hom.: 302

Bravo AF: 0.0575

Asia WGS AF: 0.0220 AC: 75 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Leber congenital amaurosis 4 (1)
-	-	1	not provided (1)
-	-	1	Retinitis Pigmentosa, Dominant (1)
-	-	1	Retinitis Pigmentosa, Recessive (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	2.4
DANN	Benign	0.81
PhyloP100		-2.6
Mutation Taster		=100/0	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: rs11869066; hg19: chr17-6327212;