17-6428497-C-T

Variant names:

• chr17-6428497-C-T
• rs62619924
• NM_014336.5:c.286G>A

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_014336.5(AIPL1):​c.286G>A​(p.Val96Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.019 in 1,613,566 control chromosomes in the GnomAD database, including 382 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V96F) has been classified as Uncertain significance. The gene AIPL1 is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.013 (23 hom., cov: 35)
  • Exomes 𝑓: 0.020 (359 hom.)
• Consequence: AIPL1 NM_014336.5 missense
• Clinical Significance: Benign reviewed by expert panel B:12 O:1
• Conservation: PhyloP100: 0.508
• Publications: 18 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 -18 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=0.006728053).
• BP6: Variant 17-6428497-C-T is Benign according to our data. Variant chr17-6428497-C-T is described in ClinVar as Benign. ClinVar VariationId is 99800.Status of the report is reviewed_by_expert_panel, 3 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0128 (1943/152342) while in subpopulation NFE AF = 0.0217 (1477/68028). AF 95% confidence interval is 0.0208. There are 23 homozygotes in GnomAd4. There are 909 alleles in the male GnomAd4 subpopulation. Median coverage is 35. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 23 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.286G>A	p.Val96Ile	missense	Exon 3 of 6	NP_055151.3
	AIPL1	NM_001285399.3		c.250G>A	p.Val84Ile	missense	Exon 3 of 6	NP_001272328.1	Q7Z3H1
	AIPL1	NM_001285400.3		c.220G>A	p.Val74Ile	missense	Exon 3 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.286G>A	p.Val96Ile	missense	Exon 3 of 6	ENSP00000370521.3	Q9NZN9-1
	AIPL1	ENST00000574506.5	TSL:1	c.250G>A	p.Val84Ile	missense	Exon 3 of 6	ENSP00000458456.1	Q7Z3H1
	AIPL1	ENST00000570466.5	TSL:1	c.220G>A	p.Val74Ile	missense	Exon 3 of 6	ENSP00000461287.1	Q9NZN9-4

Frequencies

GnomAD3 genomes AF: 0.0128 AC: 1944 AN: 152224 Hom.: 23 Cov.: 35

Gnomad AFR AF: 0.00396

Gnomad AMI AF: 0.0833

Gnomad AMR AF: 0.00595

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.00950

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0217

Gnomad OTH AF: 0.00955

GnomAD2 exomes AF: 0.0129 AC: 3221 AN: 250580 AF XY: 0.0128

Gnomad AFR exome AF: 0.00339

Gnomad AMR exome AF: 0.00454

Gnomad ASJ exome AF: 0.000993

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0105

Gnomad NFE exome AF: 0.0236

Gnomad OTH exome AF: 0.00996

GnomAD4 exome AF: 0.0196 AC: 28652 AN: 1461224 Hom.: 359 Cov.: 53 AF XY: 0.0188 AC XY: 13676 AN XY: 726904

African (AFR) AF: 0.00341 AC: 114 AN: 33476

American (AMR) AF: 0.00418 AC: 187 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00161 AC: 42 AN: 26134

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

South Asian (SAS) AF: 0.00153 AC: 132 AN: 86242

European-Finnish (FIN) AF: 0.0125 AC: 666 AN: 53140

Middle Eastern (MID) AF: 0.00243 AC: 14 AN: 5766

European-Non Finnish (NFE) AF: 0.0238 AC: 26503 AN: 1111672

Other (OTH) AF: 0.0164 AC: 993 AN: 60382

GnomAD4 genome AF: 0.0128 AC: 1943 AN: 152342 Hom.: 23 Cov.: 35 AF XY: 0.0122 AC XY: 909 AN XY: 74498

African (AFR) AF: 0.00394 AC: 164 AN: 41582

American (AMR) AF: 0.00595 AC: 91 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00202 AC: 7 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00145 AC: 7 AN: 4828

European-Finnish (FIN) AF: 0.00950 AC: 101 AN: 10630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0217 AC: 1477 AN: 68028

Other (OTH) AF: 0.00945 AC: 20 AN: 2116

Alfa AF: 0.0134 Hom.: 16

Bravo AF: 0.0118

TwinsUK AF: 0.0237 AC: 88

ALSPAC AF: 0.0275 AC: 106

ESP6500AA AF: 0.00681 AC: 30

ESP6500EA AF: 0.0217 AC: 187

ExAC AF: 0.0143 AC: 1733

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.0194

EpiControl AF: 0.0189

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (5)
-	-	3	not specified (3)
-	-	2	Leber congenital amaurosis 4 (2)
-	-	1	AIPL1-related retinopathy (1)
-	-	1	Lissencephaly due to TUBA1A mutation (1)
-	-	1	Retinitis pigmentosa;C1858386:Leber congenital amaurosis 4 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Benign	0.024	T
Eigen	Benign	-0.41
Eigen_PC	Benign	-0.30
FATHMM_MKL	Benign	0.15	N
LIST_S2	Uncertain	0.90	D
MetaRNN	Benign	0.0067	T
MetaSVM	Benign	-0.37	T
MutationAssessor	Benign	0.56	N
PhyloP100		0.51
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.010	N
REVEL	Benign	0.26
Sift	Benign	0.14	T
Sift4G	Benign	0.14	T
Polyphen		0.016	B
Vest4		0.061
MPC		0.17
ClinPred		0.0062	T
GERP RS		3.8
Varity_R		0.17
gMVP		0.43
Mutation Taster		=94/6	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: rs62619924; hg19: chr17-6331817;