rs16955851

chr17-6428382-T-A

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 2P and 12B. PM1 BP4_Strong BS1 BS2

The NM_014336.5(AIPL1):c.401A>T(p.Tyr134Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00578 in 1,612,788 control chromosomes in the GnomAD database, including 49 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. Y134Y) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0039 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0060 (47 hom.)
• Consequence: AIPL1 NM_014336.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:7
• Conservation: PhyloP100: 7.67

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 -10 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=0.024469882).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00395 (601/152328) while in subpopulation NFE AF= 0.00666 (453/68024). AF 95% confidence interval is 0.00615. There are 2 homozygotes in gnomad4. There are 272 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AIPL1	NM_014336.5	c.401A>T	p.Tyr134Phe	missense_variant	3/6	ENST00000381129.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AIPL1	ENST00000381129.8	c.401A>T	p.Tyr134Phe	missense_variant	3/6	1	NM_014336.5	P1

Frequencies

GnomAD3 genomes AF: 0.00395 AC: 601 AN: 152210 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.000989

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00471

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.00248

Gnomad FIN AF: 0.000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00666

Gnomad OTH AF: 0.00382

GnomAD3 exomes AF: 0.00401 AC: 1003 AN: 250268 Hom.: 6 AF XY: 0.00411 AC XY: 557 AN XY: 135384

Gnomad AFR exome AF: 0.00142

Gnomad AMR exome AF: 0.00289

Gnomad ASJ exome AF: 0.00149

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00281

Gnomad FIN exome AF: 0.000682

Gnomad NFE exome AF: 0.00647

Gnomad OTH exome AF: 0.00490

GnomAD4 exome AF: 0.00597 AC: 8720 AN: 1460460 Hom.: 47 Cov.: 31 AF XY: 0.00584 AC XY: 4243 AN XY: 726594

Gnomad4 AFR exome AF: 0.00116

Gnomad4 AMR exome AF: 0.00329

Gnomad4 ASJ exome AF: 0.00145

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.00364

Gnomad4 FIN exome AF: 0.000961

Gnomad4 NFE exome AF: 0.00705

Gnomad4 OTH exome AF: 0.00457

GnomAD4 genome AF: 0.00395 AC: 601 AN: 152328 Hom.: 2 Cov.: 33 AF XY: 0.00365 AC XY: 272 AN XY: 74492

Gnomad4 AFR AF: 0.000986

Gnomad4 AMR AF: 0.00471

Gnomad4 ASJ AF: 0.000865

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.00248

Gnomad4 FIN AF: 0.000941

Gnomad4 NFE AF: 0.00666

Gnomad4 OTH AF: 0.00378

Alfa AF: 0.00567 Hom.: 1

Bravo AF: 0.00402

TwinsUK AF: 0.00836 AC: 31

ALSPAC AF: 0.00934 AC: 36

ESP6500AA AF: 0.00272 AC: 12

ESP6500EA AF: 0.00686 AC: 59

ExAC AF: 0.00418 AC: 508

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00589

EpiControl AF: 0.00575

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:7

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 05, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 18, 2022	Variant summary: AIPL1 c.401A>T (p.Tyr134Phe) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.004 in 250268 control chromosomes in the gnomAD database, including 6 homozygotes. The observed variant frequency is approximately 3.58 fold of the estimated maximal expected allele frequency for a pathogenic variant in AIPL1 causing Leber Congenital Amaurosis phenotype (0.0011), strongly suggesting that the variant is benign. c.401A>T has been reported in the literature in individuals affected with Leber Congenital Amaurosis and in ethnically-matched controls (Astuti_2016). Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments: four classify as likely benign/benign while two classify as VUS. Based on the evidence outlined above, the variant was classified as benign. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 04, 2019	The p.Tyr134Phe variant in AIPL1 is classified as benign because it has been identified in 0.7% (840/129112) of European chromosomes and 6 homozygotes by gnomAD (http://gnomad.broadinstitute.org). ACMG/AMP Criteria applied: BA1. -

Leber congenital amaurosis 4 Uncertain:1 Benign:1

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Uncertain significance, 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. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

not provided Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2019	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 09, 2023	- -

Leber congenital amaurosis 1 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.029	T
BayesDel_noAF	Pathogenic	0.20
Cadd	Uncertain	24
Dann	Uncertain	0.98
DEOGEN2	Benign	0.37	T;T;.;.;.;.;T;T
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.76	T;T;T;T;T;T;T;T
M_CAP	Benign	0.054	D
MetaRNN	Benign	0.024	T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.45	D
MutationAssessor	Uncertain	2.5	M;.;.;.;M;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.68	T
PROVEAN	Uncertain	-2.4	N;.;.;.;.;.;.;.
REVEL	Pathogenic	0.84
Sift	Benign	0.12	T;.;.;.;.;.;.;.
Sift4G	Benign	0.15	T;T;T;T;T;T;T;.
Polyphen		0.66	P;.;D;.;.;P;.;.
Vest4		0.71
MVP		0.90
MPC		0.52
ClinPred		0.019	T
GERP RS		4.9
Varity_R		0.65
gMVP		0.60

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: rs16955851; hg19: chr17-6331702;