Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_ModerateBP6BP7BS1BS2

The NM_014336.5(AIPL1):c.234C>T(p.Ser78Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000266 in 1,613,838 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0010 ( 1 hom., cov: 30)

Exomes 𝑓: 0.00019 ( 2 hom. )

Consequence

AIPL1
NM_014336.5 synonymous

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:2O:1

Conservation

PhyloP100: 2.45

Publications

2 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 -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.42).

BP6

Variant 17-6433961-G-A is Benign according to our data. Variant chr17-6433961-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 99791.

BP7

Synonymous conserved (PhyloP=2.45 with no splicing effect.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.001 (152/152036) while in subpopulation AFR AF = 0.00348 (144/41358). AF 95% confidence interval is 0.00302. There are 1 homozygotes in GnomAd4. There are 81 alleles in the male GnomAd4 subpopulation. Median coverage is 30. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 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
AIPL1	NM_014336.5	MANE Select	c.234C>T	p.Ser78Ser	synonymous	Exon 2 of 6	NP_055151.3
AIPL1	NM_001285399.3		c.198C>T	p.Ser66Ser	synonymous	Exon 2 of 6	NP_001272328.1
AIPL1	NM_001285400.3		c.168C>T	p.Ser56Ser	synonymous	Exon 2 of 6	NP_001272329.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
AIPL1	ENST00000381129.8	TSL:1 MANE Select	c.234C>T	p.Ser78Ser	synonymous	Exon 2 of 6	ENSP00000370521.3
AIPL1	ENST00000574506.5	TSL:1	c.198C>T	p.Ser66Ser	synonymous	Exon 2 of 6	ENSP00000458456.1
AIPL1	ENST00000570466.5	TSL:1	c.168C>T	p.Ser56Ser	synonymous	Exon 2 of 6	ENSP00000461287.1

Frequencies

GnomAD3 genomes

AF:

0.000968

AC:

147

AN:

151918

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00335

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.000479

GnomAD2 exomes

AF:

0.000287

AC:

AN:

251118

AF XY:

0.000273

show subpopulations

Gnomad AFR exome

AF:

0.00345

Gnomad AMR exome

AF:

0.0000579

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000106

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000189

AC:

277

AN:

1461802

Hom.:

Cov.:

AF XY:

0.000194

AC XY:

141

AN XY:

727190

show subpopulations

African (AFR)

AF:

0.00457

AC:

153

AN:

33476

American (AMR)

AF:

0.000157

AC:

AN:

44710

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39692

South Asian (SAS)

AF:

0.0000464

AC:

AN:

86242

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.00243

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.0000414

AC:

AN:

1111982

Other (OTH)

AF:

0.000878

AC:

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

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

GnomAD4 genome

AF:

0.00100

AC:

152

AN:

152036

Hom.:

Cov.:

AF XY:

0.00109

AC XY:

AN XY:

74336

show subpopulations

African (AFR)

AF:

0.00348

AC:

144

AN:

41358

American (AMR)

AF:

0.000262

AC:

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5158

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

67994

Other (OTH)

AF:

0.000474

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.511

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.000494

Hom.:

Bravo

AF:

0.00101

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.000382

EpiControl

AF:

0.000237

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Leber congenital amaurosis 4 (2)

not specified (1)

Retinitis pigmentosa (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.42

CADD

Benign

7.8

(source)

DANN

Benign

0.59

PhyloP100

2.4

Mutation Taster

=87/13

polymorphism

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

NM_014336.5:c.234C>T

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

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over