17-6425710-C-A

Variant names:

• chr17-6425710-C-A
• rs62637015
• NM_014336.5:c.905G>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_014336.5(AIPL1):​c.905G>T​(p.Arg302Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00155 in 1,608,168 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). The gene AIPL1 is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.0013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0016 (11 hom.)
• Consequence: AIPL1 NM_014336.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1 B:9 O:2
• Conservation: PhyloP100: -0.221
• Publications: 23 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

Specifications for AIPL1 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0067735612).
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00125 (191/152308) while in subpopulation SAS AF = 0.0085 (41/4822). AF 95% confidence interval is 0.00644. There are 0 homozygotes in GnomAd4. There are 100 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 11 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014336.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AIPL1	NM_014336.5	MANE Select	c.905G>T	p.Arg302Leu	missense	Exon 6 of 6	NP_055151.3
	AIPL1	NM_001285399.3		c.869G>T	p.Arg290Leu	missense	Exon 6 of 6	NP_001272328.1	Q7Z3H1
	AIPL1	NM_001285400.3		c.839G>T	p.Arg280Leu	missense	Exon 6 of 6	NP_001272329.1	Q9NZN9-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AIPL1	ENST00000381129.8	TSL:1 MANE Select	c.905G>T	p.Arg302Leu	missense	Exon 6 of 6	ENSP00000370521.3	Q9NZN9-1
	AIPL1	ENST00000574506.5	TSL:1	c.869G>T	p.Arg290Leu	missense	Exon 6 of 6	ENSP00000458456.1	Q7Z3H1
	AIPL1	ENST00000570466.5	TSL:1	c.839G>T	p.Arg280Leu	missense	Exon 6 of 6	ENSP00000461287.1	Q9NZN9-4

Frequencies

GnomAD3 genomes AF: 0.00125 AC: 190 AN: 152190 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00308

Gnomad ASJ AF: 0.00461

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00829

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00100

Gnomad OTH AF: 0.00525

GnomAD2 exomes AF: 0.00261 AC: 639 AN: 244746 AF XY: 0.00296

Gnomad AFR exome AF: 0.0000617

Gnomad AMR exome AF: 0.00405

Gnomad ASJ exome AF: 0.00507

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00133

Gnomad OTH exome AF: 0.00461

GnomAD4 exome AF: 0.00158 AC: 2305 AN: 1455860 Hom.: 11 Cov.: 31 AF XY: 0.00185 AC XY: 1338 AN XY: 724624

African (AFR) AF: 0.000149 AC: 5 AN: 33476

American (AMR) AF: 0.00403 AC: 180 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00574 AC: 150 AN: 26120

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39696

South Asian (SAS) AF: 0.00936 AC: 807 AN: 86258

European-Finnish (FIN) AF: 0.0000211 AC: 1 AN: 47494

Middle Eastern (MID) AF: 0.00902 AC: 52 AN: 5766

European-Non Finnish (NFE) AF: 0.000860 AC: 956 AN: 1111970

Other (OTH) AF: 0.00253 AC: 153 AN: 60360

GnomAD4 genome AF: 0.00125 AC: 191 AN: 152308 Hom.: 0 Cov.: 32 AF XY: 0.00134 AC XY: 100 AN XY: 74480

African (AFR) AF: 0.000168 AC: 7 AN: 41572

American (AMR) AF: 0.00307 AC: 47 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00461 AC: 16 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00850 AC: 41 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00100 AC: 68 AN: 68022

Other (OTH) AF: 0.00520 AC: 11 AN: 2116

Alfa AF: 0.000973 Hom.: 4

Bravo AF: 0.00159

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000814 AC: 7

ExAC AF: 0.00261 AC: 317

Asia WGS AF: 0.00346 AC: 12 AN: 3478

EpiCase AF: 0.00207

EpiControl AF: 0.00237

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (6)
-	1	1	Leber congenital amaurosis 4 (3)
-	-	1	AIPL1-related disorder (1)
-	-	1	Leber congenital amaurosis 1 (1)
1	-	-	Myopia 25, autosomal dominant (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	14
DANN	Benign	0.96
DEOGEN2	Benign	0.26	T
Eigen	Benign	-0.94
Eigen_PC	Benign	-0.91
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.34	T
M_CAP	Benign	0.039	D
MetaRNN	Benign	0.0068	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.55	N
PhyloP100		-0.22
PrimateAI	Benign	0.29	T
PROVEAN	Uncertain	-3.4	D
REVEL	Uncertain	0.41
Sift	Benign	0.21	T
Sift4G	Benign	0.25	T
Polyphen		0.0030	B
Vest4		0.086
MVP		0.43
MPC		0.23
ClinPred		0.063	T
GERP RS		-3.9
Varity_R		0.20
gMVP		0.43
Mutation Taster		=96/4	polymorphism

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: rs62637015; hg19: chr17-6329030; COSMIC: COSV51508130; COSMIC: COSV51508130;