chr17-6434084-G-A

Variant names:

• chr17-6434084-G-A
• rs11650007
• NM_014336.5:c.111C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_014336.5(AIPL1):​c.111C>T​(p.Phe37Phe) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0262 in 1,613,834 control chromosomes in the GnomAD database, including 748 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

• Frequency:
  • Genomes: 𝑓 0.019 (58 hom., cov: 30)
  • Exomes 𝑓: 0.027 (690 hom.)
• Consequence: AIPL1 NM_014336.5 synonymous
• Clinical Significance: Benign reviewed by expert panel B:7 O:2
• Conservation: PhyloP100: 2.40
• Publications: 5 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BP6: Variant 17-6434084-G-A is Benign according to our data. Variant chr17-6434084-G-A is described in ClinVar as Benign. ClinVar VariationId is 99789.Status of the report is reviewed_by_expert_panel, 3 stars.
• BP7: Synonymous conserved (PhyloP=2.39 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0191 (2905/152166) while in subpopulation NFE AF = 0.0285 (1940/67996). AF 95% confidence interval is 0.0275. There are 58 homozygotes in GnomAd4. There are 1469 alleles in the male GnomAd4 subpopulation. Median coverage is 30. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 58 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AIPL1	NM_014336.5	MANE Select	c.111C>T	p.Phe37Phe	synonymous	Exon 2 of 6	NP_055151.3
	AIPL1	NM_001285401.3		c.111C>T	p.Phe37Phe	synonymous	Exon 2 of 6	NP_001272330.1	Q9NZN9-5
	AIPL1	NM_001033054.3		c.111C>T	p.Phe37Phe	synonymous	Exon 2 of 5	NP_001028226.1	Q9NZN9-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AIPL1	ENST00000381129.8	TSL:1 MANE Select	c.111C>T	p.Phe37Phe	synonymous	Exon 2 of 6	ENSP00000370521.3	Q9NZN9-1
	AIPL1	ENST00000576776.5	TSL:1	c.111C>T	p.Phe37Phe	synonymous	Exon 2 of 6	ENSP00000460827.1	Q9NZN9-5
	AIPL1	ENST00000250087.9	TSL:1	c.111C>T	p.Phe37Phe	synonymous	Exon 2 of 5	ENSP00000250087.5	Q9NZN9-3

Frequencies

GnomAD3 genomes AF: 0.0191 AC: 2905 AN: 152048 Hom.: 58 Cov.: 30

Gnomad AFR AF: 0.00544

Gnomad AMI AF: 0.0396

Gnomad AMR AF: 0.00701

Gnomad ASJ AF: 0.00346

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.0518

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0285

Gnomad OTH AF: 0.0149

GnomAD2 exomes AF: 0.0206 AC: 5159 AN: 250950 AF XY: 0.0205

Gnomad AFR exome AF: 0.00542

Gnomad AMR exome AF: 0.00440

Gnomad ASJ exome AF: 0.00348

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0496

Gnomad NFE exome AF: 0.0322

Gnomad OTH exome AF: 0.0229

GnomAD4 exome AF: 0.0269 AC: 39323 AN: 1461668 Hom.: 690 Cov.: 33 AF XY: 0.0261 AC XY: 19009 AN XY: 727132

African (AFR) AF: 0.00397 AC: 133 AN: 33480

American (AMR) AF: 0.00501 AC: 224 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.00386 AC: 101 AN: 26132

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

South Asian (SAS) AF: 0.00106 AC: 91 AN: 86226

European-Finnish (FIN) AF: 0.0495 AC: 2637 AN: 53316

Middle Eastern (MID) AF: 0.00399 AC: 23 AN: 5764

European-Non Finnish (NFE) AF: 0.0315 AC: 35065 AN: 1111956

Other (OTH) AF: 0.0174 AC: 1049 AN: 60394

GnomAD4 genome AF: 0.0191 AC: 2905 AN: 152166 Hom.: 58 Cov.: 30 AF XY: 0.0197 AC XY: 1469 AN XY: 74404

African (AFR) AF: 0.00542 AC: 225 AN: 41508

American (AMR) AF: 0.00700 AC: 107 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00346 AC: 12 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5164

South Asian (SAS) AF: 0.000622 AC: 3 AN: 4826

European-Finnish (FIN) AF: 0.0518 AC: 550 AN: 10610

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

European-Non Finnish (NFE) AF: 0.0285 AC: 1940 AN: 67996

Other (OTH) AF: 0.0147 AC: 31 AN: 2108

Alfa AF: 0.0238 Hom.: 43

Bravo AF: 0.0162

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.0232

EpiControl AF: 0.0237

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	2	Leber congenital amaurosis 4 (2)
-	-	2	not provided (4)
-	-	1	AIPL1-related retinopathy (1)
-	-	1	Retinitis Pigmentosa, Dominant (1)
-	-	1	Retinitis Pigmentosa, Recessive (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_noAF	Benign	-0.46
CADD	Benign	6.7
DANN	Benign	0.90
PhyloP100		2.4
Mutation Taster		=95/5	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs11650007; hg19: chr17-6337404;