chr17-6433927-C-A

Variant names:

• chr17-6433927-C-A
• rs12449580
• NM_014336.5:c.268G>T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B.

Score: 4 - Uncertain Significance

4

PM2PP3_Moderate

The NM_014336.5(AIPL1):​c.268G>T​(p.Asp90Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,456,970 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D90H) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: AIPL1 NM_014336.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.71
• Publications: 0 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: Labcorp Genetics (formerly Invitae), G2P
• Leber congenital amaurosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.87

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AIPL1	NM_014336.5	c.268G>T	p.Asp90Tyr	missense_variant	Exon 2 of 6	ENST00000381129.8	NP_055151.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AIPL1	ENST00000381129.8	c.268G>T	p.Asp90Tyr	missense_variant	Exon 2 of 6	1	NM_014336.5	ENSP00000370521.3

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1456970 Hom.: 0 Cov.: 35 AF XY: 0.00000276 AC XY: 2 AN XY: 724908

African (AFR) AF: 0.00 AC: 0 AN: 32364

American (AMR) AF: 0.00 AC: 0 AN: 44484

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26120

East Asian (EAS) AF: 0.00 AC: 0 AN: 39666

South Asian (SAS) AF: 0.00 AC: 0 AN: 86136

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53334

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5630

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1109162

Other (OTH) AF: 0.00 AC: 0 AN: 60074

GnomAD4 genome Cov.: 30

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.36
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.48	T;.;T;.;.;.;T;T
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.97	D;D;D;D;D;D;D;D
M_CAP	Uncertain	0.19	D
MetaRNN	Pathogenic	0.87	D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.82	D
MutationAssessor	Pathogenic	3.0	M;M;.;.;.;M;.;.
PhyloP100		4.7
PrimateAI	Uncertain	0.53	T
PROVEAN	Pathogenic	-7.3	D;D;.;.;.;.;.;.
REVEL	Pathogenic	0.72
Sift	Uncertain	0.0020	D;D;.;.;.;.;.;.
Sift4G	Uncertain	0.0040	D;D;D;D;D;D;D;.
Polyphen		1.0	D;D;.;D;.;.;.;.
Vest4		0.77
MutPred		0.41		Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);.;Loss of sheet (P = 0.0817);.;Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);
MVP		0.98
MPC		0.82
ClinPred		0.99	D
GERP RS		4.0
Varity_R		0.95
gMVP		0.90
Mutation Taster		=40/60	disease causing

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: rs12449580; hg19: chr17-6337247;