rs150427474

Positions:

• chr17-6425644-C-A
• chr17-6425644-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_014336.5(AIPL1):​c.971G>T​(p.Arg324Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00552 in 1,612,140 control chromosomes in the GnomAD database, including 21 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0035 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0057 (21 hom.)
• Consequence: AIPL1 NM_014336.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:4
• Conservation: PhyloP100: 1.90

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.020529807).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00349 (532/152232) while in subpopulation NFE AF= 0.00621 (422/67990). AF 95% confidence interval is 0.00572. There are 0 homozygotes in gnomad4. There are 245 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 21 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AIPL1	NM_014336.5	c.971G>T	p.Arg324Leu	missense_variant	6/6	ENST00000381129.8	NP_055151.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AIPL1	ENST00000381129.8	c.971G>T	p.Arg324Leu	missense_variant	6/6	1	NM_014336.5	ENSP00000370521	P1

Frequencies

GnomAD3 genomes AF: 0.00350 AC: 532 AN: 152114 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00135

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.00203

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00621

Gnomad OTH AF: 0.00478

GnomAD3 exomes AF: 0.00384 AC: 953 AN: 248490 Hom.: 3 AF XY: 0.00386 AC XY: 520 AN XY: 134568

Gnomad AFR exome AF: 0.000926

Gnomad AMR exome AF: 0.00315

Gnomad ASJ exome AF: 0.0000994

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00265

Gnomad FIN exome AF: 0.000693

Gnomad NFE exome AF: 0.00632

Gnomad OTH exome AF: 0.00377

GnomAD4 exome AF: 0.00573 AC: 8360 AN: 1459908 Hom.: 21 Cov.: 32 AF XY: 0.00565 AC XY: 4102 AN XY: 726368

Gnomad4 AFR exome AF: 0.000896

Gnomad4 AMR exome AF: 0.00327

Gnomad4 ASJ exome AF: 0.000191

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00218

Gnomad4 FIN exome AF: 0.000987

Gnomad4 NFE exome AF: 0.00686

Gnomad4 OTH exome AF: 0.00504

GnomAD4 genome AF: 0.00349 AC: 532 AN: 152232 Hom.: 0 Cov.: 32 AF XY: 0.00329 AC XY: 245 AN XY: 74418

Gnomad4 AFR AF: 0.00135

Gnomad4 AMR AF: 0.00203

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00166

Gnomad4 FIN AF: 0.000283

Gnomad4 NFE AF: 0.00621

Gnomad4 OTH AF: 0.00473

Alfa AF: 0.00558 Hom.: 6

Bravo AF: 0.00377

TwinsUK AF: 0.00485 AC: 18

ALSPAC AF: 0.00675 AC: 26

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00651 AC: 56

ExAC AF: 0.00383 AC: 465

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00703

EpiControl AF: 0.00747

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:3 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jun 06, 2016	The R324L variant in the AIPL1 gene has been reported previously in two individuals with a clinical diagnosis of Leber's congenital amaurosis; however, neither of these individuals had a second AIPL1 variant identified, and one individual was noted to have two reportedly pathogenic RPE65 variants also identified (Wiszniewski et al., 2011). The NHLBI ESP Exome Sequencing Project and the 1000 Genomes Project report R324L was observed in 56/8600 (0.65%) and 9/1006 (0.89%) alleles, respectively, from individuals of European background, indicating it may be a rare variant in this population. This variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties, and occurs at a position that is conserved across species. However, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret R324L as a variant of uncertain significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 22, 2016	- -
Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The AIPL1 p.Arg324Leu variant was identified in 2 of 120 proband chromosomes (frequency: 0.0167) from individuals with Leber congenital amaurosis (Wiszniewski_2011_PMID:21153841). The variant was identified in dbSNP (ID: rs150427474), ClinVar (classified as a VUS by EGL Genetics, Fulgent Genetics and GeneDx) and LOVD 3.0 (classified as a VUS and benign). The variant was also identified in control databases in 1055 of 279794 chromosomes (3 homozygous) at a frequency of 0.003771 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European (non-Finnish) in 795 of 127754 chromosomes (freq: 0.006223), Other in 26 of 7196 chromosomes (freq: 0.003613), Latino in 111 of 35420 chromosomes (freq: 0.003134), South Asian in 81 of 30602 chromosomes (freq: 0.002647), African in 25 of 24890 chromosomes (freq: 0.001004), European (Finnish) in 16 of 23664 chromosomes (freq: 0.000676) and Ashkenazi Jewish in 1 of 10350 chromosomes (freq: 0.000097), but was not observed in the East Asian population. The p.Arg324 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	AIPL1: BP4, BS2 -

Leber congenital amaurosis 4 Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	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). 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. -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

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	Uncertain	0.35
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Uncertain	-0.070
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.28	T;.;T;.;.;.
Eigen	Benign	-0.28
Eigen_PC	Benign	-0.24
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.80	T;T;T;T;T;T
M_CAP	Pathogenic	0.61	D
MetaRNN	Benign	0.021	T;T;T;T;T;T
MetaSVM	Uncertain	-0.18	T
MutationAssessor	Benign	0.55	N;.;.;.;.;.
MutationTaster	Benign	0.57	D;D;D;D;D;D;D
PrimateAI	Benign	0.36	T
PROVEAN	Uncertain	-3.1	D;D;.;.;.;.
REVEL	Uncertain	0.40
Sift	Uncertain	0.023	D;D;.;.;.;.
Sift4G	Benign	0.073	T;T;T;D;T;D
Polyphen		0.65	P;P;.;.;.;P
Vest4		0.23
MVP		0.94
MPC		0.33
ClinPred		0.048	T
GERP RS		2.7
Varity_R		0.15
gMVP		0.51

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: rs150427474; hg19: chr17-6328964;