rs144822294

Positions:

• chr17-6433951-G-A

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM1 BP4_Strong BS1_Supporting BS2

The NM_014336.5(AIPL1):​c.244C>T​(p.His82Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00166 in 1,614,082 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H82Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0013 (0 hom., cov: 30)
  • Exomes 𝑓: 0.0017 (5 hom.)
• Consequence: AIPL1 NM_014336.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:1
• Conservation: PhyloP100: 0.0720

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 -7 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 uncertain in NM_014336.5
• BP4: Computational evidence support a benign effect (MetaRNN=0.019453347).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00131 (199/152284) while in subpopulation NFE AF= 0.00197 (134/68034). AF 95% confidence interval is 0.0017. There are 0 homozygotes in gnomad4. There are 110 alleles in male gnomad4 subpopulation. Median coverage is 30. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAdExome4 at 5 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AIPL1	NM_014336.5	c.244C>T	p.His82Tyr	missense_variant	2/6	ENST00000381129.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AIPL1	ENST00000381129.8	c.244C>T	p.His82Tyr	missense_variant	2/6	1	NM_014336.5	P1

Frequencies

GnomAD3 genomes AF: 0.00131 AC: 199 AN: 152166 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00537

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00197

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.00164 AC: 411 AN: 251020 Hom.: 3 AF XY: 0.00160 AC XY: 217 AN XY: 135680

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.0000579

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000752

Gnomad FIN exome AF: 0.00602

Gnomad NFE exome AF: 0.00219

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.00170 AC: 2481 AN: 1461798 Hom.: 5 Cov.: 33 AF XY: 0.00167 AC XY: 1215 AN XY: 727186

Gnomad4 AFR exome AF: 0.000149

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.000115

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000789

Gnomad4 FIN exome AF: 0.00597

Gnomad4 NFE exome AF: 0.00181

Gnomad4 OTH exome AF: 0.00118

GnomAD4 genome AF: 0.00131 AC: 199 AN: 152284 Hom.: 0 Cov.: 30 AF XY: 0.00148 AC XY: 110 AN XY: 74450

Gnomad4 AFR AF: 0.0000963

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00537

Gnomad4 NFE AF: 0.00197

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.00156 Hom.: 1

Bravo AF: 0.000831

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00140 AC: 12

ExAC AF: 0.00185 AC: 224

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00115

EpiControl AF: 0.00148

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

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

Uncertain significance, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Aug 30, 2013

- -

Retinitis pigmentosa Uncertain:1

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). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Uncertain	-0.030
CADD	Benign	5.8
DANN	Benign	0.96
DEOGEN2	Benign	0.14	T;.;T;.;.;.;T;T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.067	N
LIST_S2	Uncertain	0.94	D;D;D;D;D;D;D;D
M_CAP	Uncertain	0.095	D
MetaRNN	Benign	0.019	T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.58	T
MutationAssessor	Benign	1.0	L;L;.;.;.;L;.;.
MutationTaster	Benign	1.0	N;N;N;N;N;N;N;N
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-1.9	N;N;.;.;.;.;.;.
REVEL	Uncertain	0.58
Sift	Uncertain	0.0090	D;T;.;.;.;.;.;.
Sift4G	Uncertain	0.0030	D;D;D;D;D;D;D;.
Polyphen		0.67	P;P;.;B;.;.;.;.
Vest4		0.72
MVP		0.79
MPC		0.42
ClinPred		0.015	T
GERP RS		-3.9
Varity_R		0.36
gMVP		0.68

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: rs144822294; hg19: chr17-6337271;