Genetic Variant NM_014336.5:c.401A>T (chr17-6428382-T-A) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_014336.5(AIPL1):c.401A>T(p.Tyr134Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00578 in 1,612,788 control chromosomes in the GnomAD database, including 49 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★). Synonymous variant affecting the same amino acid position (i.e. Y134Y) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0039 ( 2 hom., cov: 33)

Exomes 𝑓: 0.0060 ( 47 hom. )

Consequence

AIPL1
NM_014336.5 missense

Scores

Clinical Significance

Benign reviewed by expert panel U:1B:9

Conservation

PhyloP100: 7.67

Publications

8 publications found

Variant links:

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

AIPL1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.024469882).

BP6

Variant 17-6428382-T-A is Benign according to our data. Variant chr17-6428382-T-A is described in ClinVar as Benign. ClinVar VariationId is 196465.Status of the report is reviewed_by_expert_panel, 3 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00395 (601/152328) while in subpopulation NFE AF = 0.00666 (453/68024). AF 95% confidence interval is 0.00615. There are 2 homozygotes in GnomAd4. There are 272 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 2 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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
AIPL1	NM_014336.5	MANE Select	c.401A>T	p.Tyr134Phe	missense	Exon 3 of 6	NP_055151.3
AIPL1	NM_001285399.3		c.365A>T	p.Tyr122Phe	missense	Exon 3 of 6	NP_001272328.1	Q7Z3H1
AIPL1	NM_001285400.3		c.335A>T	p.Tyr112Phe	missense	Exon 3 of 6	NP_001272329.1	Q9NZN9-4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
AIPL1	ENST00000381129.8	TSL:1 MANE Select	c.401A>T	p.Tyr134Phe	missense	Exon 3 of 6	ENSP00000370521.3	Q9NZN9-1
AIPL1	ENST00000574506.5	TSL:1	c.365A>T	p.Tyr122Phe	missense	Exon 3 of 6	ENSP00000458456.1	Q7Z3H1
AIPL1	ENST00000570466.5	TSL:1	c.335A>T	p.Tyr112Phe	missense	Exon 3 of 6	ENSP00000461287.1	Q9NZN9-4

Frequencies

GnomAD3 genomes

AF:

0.00395

AC:

601

AN:

152210

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000989

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00471

Gnomad ASJ

AF:

0.000865

Gnomad EAS

AF:

0.000386

Gnomad SAS

AF:

0.00248

Gnomad FIN

AF:

0.000941

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00666

Gnomad OTH

AF:

0.00382

GnomAD2 exomes

AF:

0.00401

AC:

1003

AN:

250268

AF XY:

0.00411

show subpopulations

Gnomad AFR exome

AF:

0.00142

Gnomad AMR exome

AF:

0.00289

Gnomad ASJ exome

AF:

0.00149

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000682

Gnomad NFE exome

AF:

0.00647

Gnomad OTH exome

AF:

0.00490

GnomAD4 exome

AF:

0.00597

AC:

8720

AN:

1460460

Hom.:

Cov.:

AF XY:

0.00584

AC XY:

4243

AN XY:

726594

show subpopulations

African (AFR)

AF:

0.00116

AC:

AN:

33480

American (AMR)

AF:

0.00329

AC:

147

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00145

AC:

AN:

26136

East Asian (EAS)

AF:

0.0000756

AC:

AN:

39700

South Asian (SAS)

AF:

0.00364

AC:

314

AN:

86258

European-Finnish (FIN)

AF:

0.000961

AC:

AN:

52006

Middle Eastern (MID)

AF:

0.00139

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00705

AC:

7845

AN:

1112006

Other (OTH)

AF:

0.00457

AC:

276

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

571

1142

1712

2283

2854

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

308

616

924

1232

1540

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00395

AC:

601

AN:

152328

Hom.:

Cov.:

AF XY:

0.00365

AC XY:

272

AN XY:

74492

show subpopulations

African (AFR)

AF:

0.000986

AC:

AN:

41586

American (AMR)

AF:

0.00471

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.000865

AC:

AN:

3468

East Asian (EAS)

AF:

0.000386

AC:

AN:

5176

South Asian (SAS)

AF:

0.00248

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.000941

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00666

AC:

453

AN:

68024

Other (OTH)

AF:

0.00378

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

102

136

170

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00567

Hom.:

Bravo

AF:

0.00402

TwinsUK

AF:

0.00836

AC:

ALSPAC

AF:

0.00934

AC:

ESP6500AA

AF:

0.00272

AC:

ESP6500EA

AF:

0.00686

AC:

ExAC

AF:

0.00418

AC:

508

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00589

EpiControl

AF:

0.00575

ClinVar

ClinVar submissions

Significance:Benign

Revision:reviewed by expert panel

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (4)

Leber congenital amaurosis 4 (2)

not provided (2)

AIPL1-related retinopathy (1)

Leber congenital amaurosis 1 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.029

BayesDel_noAF

Pathogenic

0.20

CADD

Uncertain

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.37

Eigen

Uncertain

0.54

Eigen_PC

Uncertain

0.55

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.76

M_CAP

Benign

0.054

MetaRNN

Benign

0.024

MetaSVM

Uncertain

0.45

MutationAssessor

Uncertain

2.5

PhyloP100

7.7

PrimateAI

Uncertain

0.68

PROVEAN

Uncertain

-2.4

REVEL

Pathogenic

0.84

Sift

Benign

0.12

Sift4G

Benign

0.15

Polyphen

0.66

Vest4

0.71

MVP

0.90

MPC

0.52

ClinPred

0.019

GERP RS

4.9

Varity_R

0.65

gMVP

0.60

Mutation Taster

=36/64

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over