17-6433927-C-G

Variant names:

• chr17-6433927-C-G
• rs12449580
• NM_014336.5:c.268G>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_014336.5(AIPL1):​c.268G>C​(p.Asp90His) variant causes a missense change. The variant allele was found at a frequency of 0.199 in 1,603,474 control chromosomes in the GnomAD database, including 33,640 homozygotes. In-silico tool predicts 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. D90N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.19 (2802 hom., cov: 30)
  • Exomes 𝑓: 0.20 (30838 hom.)
• Consequence: AIPL1 NM_014336.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10 O:1
• Conservation: PhyloP100: 4.71
• Publications: 34 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

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.0016991198).
• BP6: Variant 17-6433927-C-G is Benign according to our data. Variant chr17-6433927-C-G is described in ClinVar as [Benign]. Clinvar id is 99794.Status of the report is reviewed_by_expert_panel, 3 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.316 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AIPL1	NM_014336.5	c.268G>C	p.Asp90His	missense_variant	Exon 2 of 6	ENST00000381129.8	NP_055151.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AIPL1	ENST00000381129.8	c.268G>C	p.Asp90His	missense_variant	Exon 2 of 6	1	NM_014336.5	ENSP00000370521.3

Frequencies

GnomAD3 genomes AF: 0.187 AC: 27366 AN: 146644 Hom.: 2803 Cov.: 30

Gnomad AFR AF: 0.0965

Gnomad AMI AF: 0.0902

Gnomad AMR AF: 0.213

Gnomad ASJ AF: 0.271

Gnomad EAS AF: 0.330

Gnomad SAS AF: 0.109

Gnomad FIN AF: 0.266

Gnomad MID AF: 0.361

Gnomad NFE AF: 0.207

Gnomad OTH AF: 0.234

GnomAD2 exomes AF: 0.209 AC: 52103 AN: 249150 AF XY: 0.204

Gnomad AFR exome AF: 0.0833

Gnomad AMR exome AF: 0.256

Gnomad ASJ exome AF: 0.293

Gnomad EAS exome AF: 0.328

Gnomad FIN exome AF: 0.248

Gnomad NFE exome AF: 0.204

Gnomad OTH exome AF: 0.223

GnomAD4 exome AF: 0.200 AC: 291904 AN: 1456726 Hom.: 30838 Cov.: 35 AF XY: 0.199 AC XY: 144384 AN XY: 724780

African (AFR) AF: 0.0863 AC: 2794 AN: 32360

American (AMR) AF: 0.249 AC: 11065 AN: 44454

Ashkenazi Jewish (ASJ) AF: 0.291 AC: 7611 AN: 26116

East Asian (EAS) AF: 0.355 AC: 14083 AN: 39646

South Asian (SAS) AF: 0.112 AC: 9681 AN: 86120

European-Finnish (FIN) AF: 0.242 AC: 12916 AN: 53320

Middle Eastern (MID) AF: 0.305 AC: 1714 AN: 5618

European-Non Finnish (NFE) AF: 0.198 AC: 219715 AN: 1109026

Other (OTH) AF: 0.205 AC: 12325 AN: 60066

GnomAD4 genome AF: 0.186 AC: 27356 AN: 146748 Hom.: 2802 Cov.: 30 AF XY: 0.188 AC XY: 13496 AN XY: 71810

African (AFR) AF: 0.0963 AC: 3583 AN: 37196

American (AMR) AF: 0.213 AC: 3201 AN: 15014

Ashkenazi Jewish (ASJ) AF: 0.271 AC: 940 AN: 3464

East Asian (EAS) AF: 0.329 AC: 1683 AN: 5120

South Asian (SAS) AF: 0.110 AC: 530 AN: 4806

European-Finnish (FIN) AF: 0.266 AC: 2802 AN: 10550

Middle Eastern (MID) AF: 0.354 AC: 104 AN: 294

European-Non Finnish (NFE) AF: 0.207 AC: 13959 AN: 67350

Other (OTH) AF: 0.230 AC: 473 AN: 2056

Alfa AF: 0.201 Hom.: 2693

Bravo AF: 0.178

TwinsUK AF: 0.186 AC: 688

ALSPAC AF: 0.192 AC: 740

ESP6500AA AF: 0.0869 AC: 383

ESP6500EA AF: 0.206 AC: 1768

ExAC AF: 0.200 AC: 24239

Asia WGS AF: 0.200 AC: 693 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3 Other:1

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Retina International

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Nov 29, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Leber congenital amaurosis 4 Benign:2

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Leber congenital amaurosis 1 Benign:1

May 28, 2019

Mendelics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Retinitis pigmentosa;C1858386:Leber congenital amaurosis 4 Benign:1

Sep 20, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Retinitis Pigmentosa, Dominant Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Retinitis pigmentosa Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.75
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Uncertain	0.040
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.37	T;.;T;.;.;.;T;T
Eigen	Benign	0.16
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.81	T;T;T;T;T;T;T;T
MetaRNN	Benign	0.0017	T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.2	T
MutationAssessor	Benign	1.9	M;M;.;.;.;M;.;.
PhyloP100		4.7
PrimateAI	Uncertain	0.55	T
PROVEAN	Pathogenic	-5.6	D;D;.;.;.;.;.;.
REVEL	Uncertain	0.61
Sift	Benign	0.057	T;D;.;.;.;.;.;.
Sift4G	Uncertain	0.0070	D;D;D;T;D;D;T;.
Polyphen		0.71	P;D;.;B;.;.;.;.
Vest4		0.31
MPC		0.63
ClinPred		0.036	T
GERP RS		4.0
Varity_R		0.67
gMVP		0.84
Mutation Taster		=51/49	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

Other links and lift over

dbSNP: rs12449580; hg19: chr17-6337247; COSMIC: COSV51505907;