17-6425489-G-C

Variant names:

• chr17-6425489-G-C
• rs61757484
• NM_014336.5:c.1126C>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_014336.5(AIPL1):​c.1126C>G​(p.Pro376Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000436 in 1,605,394 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P376S) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: AIPL1 NM_014336.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -4.46
• Publications: 12 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: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.11474463).

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.1126C>G	p.Pro376Ala	missense	Exon 6 of 6	NP_055151.3
	AIPL1	NM_001285399.3		c.1090C>G	p.Pro364Ala	missense	Exon 6 of 6	NP_001272328.1	Q7Z3H1
	AIPL1	NM_001285400.3		c.1060C>G	p.Pro354Ala	missense	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.1126C>G	p.Pro376Ala	missense	Exon 6 of 6	ENSP00000370521.3	Q9NZN9-1
	AIPL1	ENST00000574506.5	TSL:1	c.1090C>G	p.Pro364Ala	missense	Exon 6 of 6	ENSP00000458456.1	Q7Z3H1
	AIPL1	ENST00000570466.5	TSL:1	c.1060C>G	p.Pro354Ala	missense	Exon 6 of 6	ENSP00000461287.1	Q9NZN9-4

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152038 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000967

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1453356 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 723092

African (AFR) AF: 0.0000300 AC: 1 AN: 33356

American (AMR) AF: 0.00 AC: 0 AN: 44666

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26068

East Asian (EAS) AF: 0.00 AC: 0 AN: 39628

South Asian (SAS) AF: 0.00 AC: 0 AN: 86178

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47138

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5668

European-Non Finnish (NFE) AF: 9.01e-7 AC: 1 AN: 1110406

Other (OTH) AF: 0.0000166 AC: 1 AN: 60248

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152038 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74266

African (AFR) AF: 0.0000967 AC: 4 AN: 41346

American (AMR) AF: 0.00 AC: 0 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68020

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.050
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	0.0070
DANN	Benign	0.12
DEOGEN2	Benign	0.028	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.0051	N
LIST_S2	Benign	0.70	T
M_CAP	Benign	0.0057	T
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-0.65	T
MutationAssessor	Benign	0.34	N
PhyloP100		-4.5
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.29	N
REVEL	Benign	0.14
Sift	Benign	0.25	T
Sift4G	Benign	0.35	T
Polyphen		0.0010	B
Vest4		0.17
MutPred		0.34		Loss of glycosylation at P376 (P = 0.0091)
MVP		0.87
MPC		0.18
ClinPred		0.20	T
GERP RS		0.52
Varity_R		0.023
gMVP		0.17
Mutation Taster		=100/0	polymorphism

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: rs61757484; hg19: chr17-6328809;