rs61757484

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr17-6425489-G-A
• chr17-6425489-G-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.1126C>T​(p.Pro376Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00336 in 1,605,510 control chromosomes in the GnomAD database, including 170 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P376L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.018 (89 hom., cov: 32)
  • Exomes 𝑓: 0.0019 (81 hom.)
• Consequence: AIPL1 NM_014336.5 missense
• Clinical Significance: Benign reviewed by expert panel B:12 O:2
• 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0032194257).
• BP6: Variant 17-6425489-G-A is Benign according to our data. Variant chr17-6425489-G-A is described in ClinVar as Benign. ClinVar VariationId is 65708.Status of the report is reviewed_by_expert_panel, 3 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0589 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.1126C>T	p.Pro376Ser	missense	Exon 6 of 6	NP_055151.3
	AIPL1	NM_001285399.3		c.1090C>T	p.Pro364Ser	missense	Exon 6 of 6	NP_001272328.1	Q7Z3H1
	AIPL1	NM_001285400.3		c.1060C>T	p.Pro354Ser	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>T	p.Pro376Ser	missense	Exon 6 of 6	ENSP00000370521.3	Q9NZN9-1
	AIPL1	ENST00000574506.5	TSL:1	c.1090C>T	p.Pro364Ser	missense	Exon 6 of 6	ENSP00000458456.1	Q7Z3H1
	AIPL1	ENST00000570466.5	TSL:1	c.1060C>T	p.Pro354Ser	missense	Exon 6 of 6	ENSP00000461287.1	Q9NZN9-4

Frequencies

GnomAD3 genomes AF: 0.0176 AC: 2673 AN: 152036 Hom.: 88 Cov.: 32

Gnomad AFR AF: 0.0609

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00694

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000338

Gnomad OTH AF: 0.0110

GnomAD2 exomes AF: 0.00475 AC: 1160 AN: 244098 AF XY: 0.00345

Gnomad AFR exome AF: 0.0642

Gnomad AMR exome AF: 0.00275

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000223

Gnomad OTH exome AF: 0.00199

GnomAD4 exome AF: 0.00187 AC: 2713 AN: 1453356 Hom.: 81 Cov.: 32 AF XY: 0.00161 AC XY: 1163 AN XY: 723092

African (AFR) AF: 0.0650 AC: 2169 AN: 33356

American (AMR) AF: 0.00284 AC: 127 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: 0.000197 AC: 17 AN: 86178

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

Middle Eastern (MID) AF: 0.00282 AC: 16 AN: 5668

European-Non Finnish (NFE) AF: 0.000134 AC: 149 AN: 1110406

Other (OTH) AF: 0.00390 AC: 235 AN: 60248

GnomAD4 genome AF: 0.0176 AC: 2680 AN: 152154 Hom.: 89 Cov.: 32 AF XY: 0.0171 AC XY: 1275 AN XY: 74394

African (AFR) AF: 0.0609 AC: 2526 AN: 41466

American (AMR) AF: 0.00693 AC: 106 AN: 15286

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4820

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

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

European-Non Finnish (NFE) AF: 0.000338 AC: 23 AN: 68012

Other (OTH) AF: 0.0109 AC: 23 AN: 2112

Alfa AF: 0.00414 Hom.: 1

Bravo AF: 0.0202

ESP6500AA AF: 0.0611 AC: 269

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00576 AC: 699

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.000237

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (4)
-	-	2	Leber congenital amaurosis 4 (3)
-	-	2	not specified (2)
-	-	1	AIPL1-related retinopathy (1)
-	-	1	Retinal dystrophy (1)
-	-	1	Retinitis pigmentosa (1)
-	-	1	Retinitis Pigmentosa, Dominant (1)
-	-	1	Retinitis pigmentosa;C1858386:Leber congenital amaurosis 4 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	0.025
DANN	Benign	0.29
DEOGEN2	Benign	0.020	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.0019	N
LIST_S2	Benign	0.71	T
MetaRNN	Benign	0.0032	T
MetaSVM	Benign	-0.78	T
MutationAssessor	Benign	0.34	N
PhyloP100		-4.5
PrimateAI	Benign	0.26	T
PROVEAN	Benign	0.050	N
REVEL	Benign	0.13
Sift	Benign	0.15	T
Sift4G	Benign	0.15	T
Polyphen		0.0010	B
Vest4		0.13
MVP		0.88
MPC		0.19
ClinPred		0.0022	T
GERP RS		0.52
Varity_R		0.023
gMVP		0.29
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: rs61757484; hg19: chr17-6328809; COSMIC: COSV106333272; COSMIC: COSV106333272;