rs8069375

Positions:

• chr17-6428442-G-A

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BA1

The NM_014336.5(AIPL1):​c.341C>T​(p.Thr114Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00306 in 1,613,962 control chromosomes in the GnomAD database, including 127 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.016 (76 hom., cov: 33)
  • Exomes 𝑓: 0.0017 (51 hom.)
• Consequence: AIPL1 NM_014336.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8 O:1
• Conservation: PhyloP100: 4.83

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 -18 ACMG points.

• PM1: In a domain PPIase FKBP-type (size 92) in uniprot entity AIPL1_HUMAN there are 24 pathogenic changes around while only 7 benign (77%) in NM_014336.5
• BP4: Computational evidence support a benign effect (MetaRNN=0.005100429).
• BP6: Variant 17-6428442-G-A is Benign according to our data. Variant chr17-6428442-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 99801.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-6428442-G-A is described in Lovd as [Likely_pathogenic]. Variant chr17-6428442-G-A is described in Lovd as [Likely_benign]. Variant chr17-6428442-G-A is described in Lovd as [Pathogenic].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0545 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AIPL1	NM_014336.5	c.341C>T	p.Thr114Ile	missense_variant	3/6	ENST00000381129.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AIPL1	ENST00000381129.8	c.341C>T	p.Thr114Ile	missense_variant	3/6	1	NM_014336.5	P1

Frequencies

GnomAD3 genomes AF: 0.0162 AC: 2466 AN: 152236 Hom.: 74 Cov.: 33

Gnomad AFR AF: 0.0564

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00609

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000413

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000220

Gnomad OTH AF: 0.00861

GnomAD3 exomes AF: 0.00412 AC: 1034 AN: 251086 Hom.: 28 AF XY: 0.00289 AC XY: 393 AN XY: 135756

Gnomad AFR exome AF: 0.0564

Gnomad AMR exome AF: 0.00234

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000294

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000132

Gnomad OTH exome AF: 0.00196

GnomAD4 exome AF: 0.00169 AC: 2466 AN: 1461608 Hom.: 51 Cov.: 31 AF XY: 0.00143 AC XY: 1038 AN XY: 727120

Gnomad4 AFR exome AF: 0.0599

Gnomad4 AMR exome AF: 0.00262

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000683

Gnomad4 OTH exome AF: 0.00379

GnomAD4 genome AF: 0.0162 AC: 2475 AN: 152354 Hom.: 76 Cov.: 33 AF XY: 0.0159 AC XY: 1184 AN XY: 74496

Gnomad4 AFR AF: 0.0564

Gnomad4 AMR AF: 0.00608

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000220

Gnomad4 OTH AF: 0.00852

Alfa AF: 0.00291 Hom.: 20

Bravo AF: 0.0186

ESP6500AA AF: 0.0570 AC: 251

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00513 AC: 623

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000178

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 28, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 18, 2022	- -

Leber congenital amaurosis 4 Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

not provided Benign:1 Other:1

not provided, no classification provided	literature only	Retina International	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 13, 2019	This variant is associated with the following publications: (PMID: 10873396, 33067476, 27884173, 20981092) -

Retinitis Pigmentosa, Recessive Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Retinitis pigmentosa;C1858386:Leber congenital amaurosis 4 Benign:1

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 05, 2022

- -

Retinitis pigmentosa Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Uncertain	-0.060
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.035	T;T;.;.;.;.;T;T
Eigen	Uncertain	0.24
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Uncertain	0.95	D;D;D;D;D;D;D;D
MetaRNN	Benign	0.0051	T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.28	T
MutationAssessor	Benign	1.9	L;.;.;.;L;.;.;.
MutationTaster	Benign	0.99	D;D;D;D;D;D;D;D
PrimateAI	Benign	0.44	T
PROVEAN	Benign	0.080	N;.;.;.;.;.;.;.
REVEL	Uncertain	0.50
Sift	Benign	0.19	T;.;.;.;.;.;.;.
Sift4G	Benign	0.18	T;T;T;T;T;T;T;.
Polyphen		0.63	P;.;P;.;.;P;.;.
Vest4		0.30
MVP		0.96
MPC		0.39
ClinPred		0.030	T
GERP RS		4.8
Varity_R		0.18
gMVP		0.39

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: rs8069375; hg19: chr17-6331762; COSMIC: COSV51507954;