chr17-6426833-C-T

Variant names:

• chr17-6426833-C-T
• rs925616
• NM_014336.5:c.642+48G>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.642+48G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.363 in 1,612,774 control chromosomes in the GnomAD database, including 107,303 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

• Frequency:
  • Genomes: 𝑓 0.36 (10052 hom., cov: 33)
  • Exomes 𝑓: 0.36 (97251 hom.)
• Consequence: AIPL1 NM_014336.5 intron
• Clinical Significance: Benign reviewed by expert panel B:3
• Conservation: PhyloP100: -1.63
• Publications: 9 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=-0.9).
• BP6: Variant 17-6426833-C-T is Benign according to our data. Variant chr17-6426833-C-T is described in ClinVar as Benign. ClinVar VariationId is 1239041.Status of the report is reviewed_by_expert_panel, 3 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.452 is higher than 0.05.

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.642+48G>A		intron	N/A	NP_055151.3
	AIPL1	NM_001285399.3		c.606+48G>A		intron	N/A	NP_001272328.1	Q7Z3H1
	AIPL1	NM_001285400.3		c.576+48G>A		intron	N/A	NP_001272329.1	Q9NZN9-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AIPL1	ENST00000381129.8	TSL:1 MANE Select	c.642+48G>A		intron	N/A	ENSP00000370521.3	Q9NZN9-1
	AIPL1	ENST00000574506.5	TSL:1	c.606+48G>A		intron	N/A	ENSP00000458456.1	Q7Z3H1
	AIPL1	ENST00000570466.5	TSL:1	c.576+48G>A		intron	N/A	ENSP00000461287.1	Q9NZN9-4

Frequencies

GnomAD3 genomes AF: 0.362 AC: 54959 AN: 151928 Hom.: 10038 Cov.: 33

Gnomad AFR AF: 0.344

Gnomad AMI AF: 0.175

Gnomad AMR AF: 0.317

Gnomad ASJ AF: 0.398

Gnomad EAS AF: 0.469

Gnomad SAS AF: 0.299

Gnomad FIN AF: 0.421

Gnomad MID AF: 0.525

Gnomad NFE AF: 0.369

Gnomad OTH AF: 0.385

GnomAD2 exomes AF: 0.363 AC: 90736 AN: 249752 AF XY: 0.361

Gnomad AFR exome AF: 0.346

Gnomad AMR exome AF: 0.323

Gnomad ASJ exome AF: 0.417

Gnomad EAS exome AF: 0.462

Gnomad FIN exome AF: 0.416

Gnomad NFE exome AF: 0.366

Gnomad OTH exome AF: 0.382

GnomAD4 exome AF: 0.363 AC: 530076 AN: 1460730 Hom.: 97251 Cov.: 44 AF XY: 0.362 AC XY: 262921 AN XY: 726718

African (AFR) AF: 0.350 AC: 11711 AN: 33480

American (AMR) AF: 0.320 AC: 14305 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.414 AC: 10817 AN: 26128

East Asian (EAS) AF: 0.477 AC: 18927 AN: 39698

South Asian (SAS) AF: 0.290 AC: 25021 AN: 86244

European-Finnish (FIN) AF: 0.408 AC: 21433 AN: 52526

Middle Eastern (MID) AF: 0.471 AC: 2713 AN: 5764

European-Non Finnish (NFE) AF: 0.362 AC: 402553 AN: 1111800

Other (OTH) AF: 0.374 AC: 22596 AN: 60376

GnomAD4 genome AF: 0.362 AC: 55005 AN: 152044 Hom.: 10052 Cov.: 33 AF XY: 0.363 AC XY: 26966 AN XY: 74326

African (AFR) AF: 0.345 AC: 14292 AN: 41474

American (AMR) AF: 0.317 AC: 4844 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.398 AC: 1380 AN: 3466

East Asian (EAS) AF: 0.468 AC: 2411 AN: 5152

South Asian (SAS) AF: 0.299 AC: 1441 AN: 4822

European-Finnish (FIN) AF: 0.421 AC: 4461 AN: 10584

Middle Eastern (MID) AF: 0.517 AC: 152 AN: 294

European-Non Finnish (NFE) AF: 0.369 AC: 25053 AN: 67952

Other (OTH) AF: 0.385 AC: 812 AN: 2108

Alfa AF: 0.303 Hom.: 1258

Bravo AF: 0.356

Asia WGS AF: 0.391 AC: 1356 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	AIPL1-related retinopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.27
DANN	Benign	0.67
PhyloP100		-1.6
Mutation Taster		=100/0	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: rs925616; hg19: chr17-6330153; COSMIC: COSV51506326; COSMIC: COSV51506326;