NM_014336.5:c.-106C>A

Variant names:

• chr17-6435210-G-T
• rs7211442
• NM_014336.5:c.-106C>A

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.-106C>A variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.111 in 1,492,424 control chromosomes in the GnomAD database, including 11,331 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.10 (1047 hom., cov: 32)
  • Exomes 𝑓: 0.11 (10284 hom.)
• Consequence: AIPL1 NM_014336.5 upstream_gene
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.559
• Publications: 3 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 (BayesDel_noAF=-0.87).
• BP6: Variant 17-6435210-G-T is Benign according to our data. Variant chr17-6435210-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 369221.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.279 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AIPL1	NM_014336.5	c.-106C>A		upstream_gene_variant		ENST00000381129.8	NP_055151.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AIPL1	ENST00000381129.8	c.-106C>A		upstream_gene_variant		1	NM_014336.5	ENSP00000370521.3

Frequencies

GnomAD3 genomes AF: 0.104 AC: 15868 AN: 152016 Hom.: 1047 Cov.: 32

Gnomad AFR AF: 0.0545

Gnomad AMI AF: 0.0242

Gnomad AMR AF: 0.154

Gnomad ASJ AF: 0.224

Gnomad EAS AF: 0.293

Gnomad SAS AF: 0.0892

Gnomad FIN AF: 0.0951

Gnomad MID AF: 0.275

Gnomad NFE AF: 0.105

Gnomad OTH AF: 0.143

GnomAD4 exome AF: 0.112 AC: 149849 AN: 1340288 Hom.: 10284 Cov.: 20 AF XY: 0.113 AC XY: 74960 AN XY: 666248

African (AFR) AF: 0.0538 AC: 1643 AN: 30528

American (AMR) AF: 0.206 AC: 7544 AN: 36702

Ashkenazi Jewish (ASJ) AF: 0.240 AC: 5955 AN: 24798

East Asian (EAS) AF: 0.334 AC: 11954 AN: 35784

South Asian (SAS) AF: 0.0928 AC: 7399 AN: 79746

European-Finnish (FIN) AF: 0.0853 AC: 3556 AN: 41690

Middle Eastern (MID) AF: 0.252 AC: 1402 AN: 5560

European-Non Finnish (NFE) AF: 0.101 AC: 103477 AN: 1029238

Other (OTH) AF: 0.123 AC: 6919 AN: 56242

GnomAD4 genome AF: 0.104 AC: 15863 AN: 152136 Hom.: 1047 Cov.: 32 AF XY: 0.106 AC XY: 7846 AN XY: 74362

African (AFR) AF: 0.0544 AC: 2258 AN: 41532

American (AMR) AF: 0.155 AC: 2366 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.224 AC: 777 AN: 3468

East Asian (EAS) AF: 0.291 AC: 1494 AN: 5134

South Asian (SAS) AF: 0.0899 AC: 433 AN: 4818

European-Finnish (FIN) AF: 0.0951 AC: 1009 AN: 10612

Middle Eastern (MID) AF: 0.276 AC: 81 AN: 294

European-Non Finnish (NFE) AF: 0.105 AC: 7126 AN: 67976

Other (OTH) AF: 0.141 AC: 297 AN: 2110

Alfa AF: 0.113 Hom.: 1870

Bravo AF: 0.113

Asia WGS AF: 0.168 AC: 581 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jul 11, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Retinitis Pigmentosa, Recessive Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Leber congenital amaurosis Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely 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

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	5.9
DANN	Benign	0.66
PhyloP100		0.56
PromoterAI		-0.018	Neutral
Mutation Taster		=100/0	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs7211442; hg19: chr17-6338530; COSMIC: COSV51507822;