rs907938

Variant names:

• chr17-6424231-G-A
• rs907938
• NM_014336.5:c.*1229C>T

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.*1229C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.284 in 152,172 control chromosomes in the GnomAD database, including 6,263 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.28 (6258 hom., cov: 33)
  • Exomes 𝑓: 0.32 (5 hom.)
• Consequence: AIPL1 NM_014336.5 3_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.539
• Publications: 6 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=-1.0).
• BP6: Variant 17-6424231-G-A is Benign according to our data. Variant chr17-6424231-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 324581.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.344 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.*1229C>T		3_prime_UTR	Exon 6 of 6	NP_055151.3
	AIPL1	NM_001285399.3		c.*1229C>T		3_prime_UTR	Exon 6 of 6	NP_001272328.1	Q7Z3H1
	AIPL1	NM_001285400.3		c.*1229C>T		3_prime_UTR	Exon 6 of 6	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.*1229C>T		3_prime_UTR	Exon 6 of 6	ENSP00000370521.3	Q9NZN9-1
	AIPL1	ENST00000250087.9	TSL:1	c.*1229C>T		3_prime_UTR	Exon 5 of 5	ENSP00000250087.5	Q9NZN9-3
	AIPL1	ENST00000381128.2	TSL:1	n.*2256C>T		non_coding_transcript_exon	Exon 6 of 6	ENSP00000370520.2	J3KPI5

Frequencies

GnomAD3 genomes AF: 0.284 AC: 43169 AN: 151982 Hom.: 6250 Cov.: 33

Gnomad AFR AF: 0.240

Gnomad AMI AF: 0.474

Gnomad AMR AF: 0.314

Gnomad ASJ AF: 0.305

Gnomad EAS AF: 0.281

Gnomad SAS AF: 0.358

Gnomad FIN AF: 0.270

Gnomad MID AF: 0.275

Gnomad NFE AF: 0.298

Gnomad OTH AF: 0.280

GnomAD4 exome AF: 0.319 AC: 23 AN: 72 Hom.: 5 Cov.: 0 AF XY: 0.357 AC XY: 20 AN XY: 56

African (AFR) AF: 0.00 AC: 0 AN: 4

American (AMR) AF: 0.500 AC: 1 AN: 2

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2

East Asian (EAS) AF: 0.500 AC: 4 AN: 8

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.500 AC: 1 AN: 2

Middle Eastern (MID) AF: 1.00 AC: 2 AN: 2

European-Non Finnish (NFE) AF: 0.292 AC: 14 AN: 48

Other (OTH) AF: 0.250 AC: 1 AN: 4

GnomAD4 genome AF: 0.284 AC: 43212 AN: 152100 Hom.: 6258 Cov.: 33 AF XY: 0.285 AC XY: 21211 AN XY: 74338

African (AFR) AF: 0.240 AC: 9954 AN: 41512

American (AMR) AF: 0.314 AC: 4801 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.305 AC: 1055 AN: 3464

East Asian (EAS) AF: 0.280 AC: 1449 AN: 5168

South Asian (SAS) AF: 0.358 AC: 1728 AN: 4824

European-Finnish (FIN) AF: 0.270 AC: 2860 AN: 10578

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

European-Non Finnish (NFE) AF: 0.298 AC: 20254 AN: 67960

Other (OTH) AF: 0.284 AC: 599 AN: 2108

Alfa AF: 0.294 Hom.: 11162

Bravo AF: 0.283

Asia WGS AF: 0.309 AC: 1077 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Leber congenital amaurosis 4 (1)
-	-	1	not provided (1)
-	-	1	Retinitis pigmentosa (1)
-	-	1	Retinitis Pigmentosa, Dominant (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	3.4
DANN	Benign	0.35
PhyloP100		-0.54
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: rs907938; hg19: chr17-6327551; COSMIC: COSV51508691; COSMIC: COSV51508691;