chr17-6428516-T-G

Variant names:

• chr17-6428516-T-G
• rs12453262
• NM_014336.5:c.277-10A>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.277-10A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.56 in 1,611,246 control chromosomes in the GnomAD database, including 256,149 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.53 (21911 hom., cov: 34)
  • Exomes 𝑓: 0.56 (234238 hom.)
• Consequence: AIPL1 NM_014336.5 intron
• Scores: Splicing: ADA: 0.00001746
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10 O:1
• Conservation: PhyloP100: -0.0900
• Publications: 11 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=-0.88).
• BP6: Variant 17-6428516-T-G is Benign according to our data. Variant chr17-6428516-T-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 99796.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.601 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.277-10A>C		intron	N/A	NP_055151.3
	AIPL1	NM_001285399.3		c.241-10A>C		intron	N/A	NP_001272328.1	Q7Z3H1
	AIPL1	NM_001285400.3		c.211-10A>C		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.277-10A>C		intron	N/A	ENSP00000370521.3	Q9NZN9-1
	AIPL1	ENST00000574506.5	TSL:1	c.241-10A>C		intron	N/A	ENSP00000458456.1	Q7Z3H1
	AIPL1	ENST00000570466.5	TSL:1	c.211-10A>C		intron	N/A	ENSP00000461287.1	Q9NZN9-4

Frequencies

GnomAD3 genomes AF: 0.527 AC: 80055 AN: 151996 Hom.: 21901 Cov.: 34

Gnomad AFR AF: 0.383

Gnomad AMI AF: 0.462

Gnomad AMR AF: 0.611

Gnomad ASJ AF: 0.716

Gnomad EAS AF: 0.497

Gnomad SAS AF: 0.516

Gnomad FIN AF: 0.551

Gnomad MID AF: 0.747

Gnomad NFE AF: 0.583

Gnomad OTH AF: 0.590

GnomAD2 exomes AF: 0.566 AC: 141360 AN: 249608 AF XY: 0.567

Gnomad AFR exome AF: 0.377

Gnomad AMR exome AF: 0.656

Gnomad ASJ exome AF: 0.720

Gnomad EAS exome AF: 0.504

Gnomad FIN exome AF: 0.552

Gnomad NFE exome AF: 0.577

Gnomad OTH exome AF: 0.600

GnomAD4 exome AF: 0.564 AC: 822435 AN: 1459132 Hom.: 234238 Cov.: 44 AF XY: 0.563 AC XY: 409098 AN XY: 726038

African (AFR) AF: 0.377 AC: 12583 AN: 33420

American (AMR) AF: 0.649 AC: 29025 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.722 AC: 18846 AN: 26116

East Asian (EAS) AF: 0.497 AC: 19736 AN: 39678

South Asian (SAS) AF: 0.522 AC: 45004 AN: 86192

European-Finnish (FIN) AF: 0.549 AC: 28999 AN: 52862

Middle Eastern (MID) AF: 0.713 AC: 4113 AN: 5768

European-Non Finnish (NFE) AF: 0.567 AC: 629567 AN: 1110088

Other (OTH) AF: 0.573 AC: 34562 AN: 60300

GnomAD4 genome AF: 0.527 AC: 80107 AN: 152114 Hom.: 21911 Cov.: 34 AF XY: 0.525 AC XY: 39051 AN XY: 74330

African (AFR) AF: 0.384 AC: 15922 AN: 41510

American (AMR) AF: 0.611 AC: 9344 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.716 AC: 2483 AN: 3468

East Asian (EAS) AF: 0.496 AC: 2554 AN: 5154

South Asian (SAS) AF: 0.516 AC: 2492 AN: 4826

European-Finnish (FIN) AF: 0.551 AC: 5832 AN: 10590

Middle Eastern (MID) AF: 0.748 AC: 220 AN: 294

European-Non Finnish (NFE) AF: 0.583 AC: 39598 AN: 67970

Other (OTH) AF: 0.589 AC: 1242 AN: 2108

Alfa AF: 0.578 Hom.: 44144

Bravo AF: 0.526

Asia WGS AF: 0.486 AC: 1691 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	Leber congenital amaurosis 4 (2)
-	-	2	not provided (3)
-	-	1	Retinitis pigmentosa (1)
-	-	1	Retinitis Pigmentosa, Recessive (1)
-	-	1	Retinitis pigmentosa;C1858386:Leber congenital amaurosis 4 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	2.5
DANN	Benign	0.69
PhyloP100		-0.090
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000017
dbscSNV1_RF	Benign	0.0020
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: rs12453262; hg19: chr17-6331836; COSMIC: COSV51506213;