rs8069375

Variant names:

• chr17-6428442-G-A
• rs8069375
• NM_014336.5:c.341C>T
• AIPL1 p.Thr114Ile

Your query was ambiguous. Multiple possible variants found:

• chr17-6428442-G-A
• chr17-6428442-G-T

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BA1

The NM_014336.5(AIPL1):​c.341C>T​(p.Thr114Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00306 in 1,613,962 control chromosomes in the GnomAD database, including 127 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★). The gene AIPL1 is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.016 (76 hom., cov: 33)
  • Exomes 𝑓: 0.0017 (51 hom.)
• Consequence: AIPL1 NM_014336.5 missense
• Clinical Significance: Benign reviewed by expert panel B:11 O:1
• Conservation: PhyloP100: 4.83
• Publications: 12 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, 7 uncertain in NM_014336.5
• BP4: Computational evidence support a benign effect (MetaRNN=0.005100429).
• BP6: Variant 17-6428442-G-A is Benign according to our data. Variant chr17-6428442-G-A is described in ClinVar as Benign. ClinVar VariationId is 99801.Status of the report is reviewed_by_expert_panel, 3 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0545 is higher than 0.05.

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.341C>T	p.Thr114Ile	missense	Exon 3 of 6	NP_055151.3
	AIPL1	NM_001285399.3		c.305C>T	p.Thr102Ile	missense	Exon 3 of 6	NP_001272328.1	Q7Z3H1
	AIPL1	NM_001285400.3		c.275C>T	p.Thr92Ile	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.341C>T	p.Thr114Ile	missense	Exon 3 of 6	ENSP00000370521.3	Q9NZN9-1
	AIPL1	ENST00000574506.5	TSL:1	c.305C>T	p.Thr102Ile	missense	Exon 3 of 6	ENSP00000458456.1	Q7Z3H1
	AIPL1	ENST00000570466.5	TSL:1	c.275C>T	p.Thr92Ile	missense	Exon 3 of 6	ENSP00000461287.1	Q9NZN9-4

Frequencies

GnomAD3 genomes AF: 0.0162 AC: 2466 AN: 152236 Hom.: 74 Cov.: 33

Gnomad AFR AF: 0.0564

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00609

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000413

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000220

Gnomad OTH AF: 0.00861

GnomAD2 exomes AF: 0.00412 AC: 1034 AN: 251086 AF XY: 0.00289

Gnomad AFR exome AF: 0.0564

Gnomad AMR exome AF: 0.00234

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000132

Gnomad OTH exome AF: 0.00196

GnomAD4 exome AF: 0.00169 AC: 2466 AN: 1461608 Hom.: 51 Cov.: 31 AF XY: 0.00143 AC XY: 1038 AN XY: 727120

African (AFR) AF: 0.0599 AC: 2005 AN: 33476

American (AMR) AF: 0.00262 AC: 117 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000232 AC: 20 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53144

Middle Eastern (MID) AF: 0.00329 AC: 19 AN: 5768

European-Non Finnish (NFE) AF: 0.0000683 AC: 76 AN: 1112010

Other (OTH) AF: 0.00379 AC: 229 AN: 60392

GnomAD4 genome AF: 0.0162 AC: 2475 AN: 152354 Hom.: 76 Cov.: 33 AF XY: 0.0159 AC XY: 1184 AN XY: 74496

African (AFR) AF: 0.0564 AC: 2346 AN: 41588

American (AMR) AF: 0.00608 AC: 93 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

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

European-Non Finnish (NFE) AF: 0.000220 AC: 15 AN: 68042

Other (OTH) AF: 0.00852 AC: 18 AN: 2112

Alfa AF: 0.00633 Hom.: 52

Bravo AF: 0.0186

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000178

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	2	Leber congenital amaurosis 4 (2)
-	-	2	not provided (3)
-	-	2	not specified (2)
-	-	1	AIPL1-related retinopathy (1)
-	-	1	Retinal dystrophy (1)
-	-	1	Retinitis pigmentosa (1)
-	-	1	Retinitis Pigmentosa, Recessive (1)
-	-	1	Retinitis pigmentosa;C1858386:Leber congenital amaurosis 4 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Uncertain	-0.060
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.035	T
Eigen	Uncertain	0.24
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Uncertain	0.95	D
MetaRNN	Benign	0.0051	T
MetaSVM	Benign	-0.28	T
MutationAssessor	Benign	1.9	L
PhyloP100		4.8
PrimateAI	Benign	0.44	T
PROVEAN	Benign	0.080	N
REVEL	Uncertain	0.50
Sift	Benign	0.19	T
Sift4G	Benign	0.18	T
Varity_R		0.18
gMVP		0.39
Mutation Taster		=96/4	polymorphism (auto)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs8069375;

hg19: chr17-6331762;

COSMIC: COSV51507954;