rs12449580

Variant names:

• chr17-6433927-C-G
• rs12449580
• NM_014336.5:c.268G>C

Your query was ambiguous. Multiple possible variants found:

• chr17-6433927-C-G
• chr17-6433927-C-T
• chr17-6433927-C-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.268G>C​(p.Asp90His) variant causes a missense change. The variant allele was found at a frequency of 0.199 in 1,603,474 control chromosomes in the GnomAD database, including 33,640 homozygotes. In-silico tool predicts 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. D90N) has been classified as Uncertain significance. The gene AIPL1 is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.19 (2802 hom., cov: 30)
  • Exomes 𝑓: 0.20 (30838 hom.)
• Consequence: AIPL1 NM_014336.5 missense
• Clinical Significance: Benign reviewed by expert panel B:11 O:1
• Conservation: PhyloP100: 4.71
• Publications: 34 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

Specifications for AIPL1 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0016991198).
• BP6: Variant 17-6433927-C-G is Benign according to our data. Variant chr17-6433927-C-G is described in ClinVar as Benign. ClinVar VariationId is 99794.Status of the report is reviewed_by_expert_panel, 3 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.316 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.268G>C	p.Asp90His	missense	Exon 2 of 6	NP_055151.3
	AIPL1	NM_001285399.3		c.232G>C	p.Asp78His	missense	Exon 2 of 6	NP_001272328.1	Q7Z3H1
	AIPL1	NM_001285400.3		c.202G>C	p.Asp68His	missense	Exon 2 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.268G>C	p.Asp90His	missense	Exon 2 of 6	ENSP00000370521.3	Q9NZN9-1
	AIPL1	ENST00000574506.5	TSL:1	c.232G>C	p.Asp78His	missense	Exon 2 of 6	ENSP00000458456.1	Q7Z3H1
	AIPL1	ENST00000570466.5	TSL:1	c.202G>C	p.Asp68His	missense	Exon 2 of 6	ENSP00000461287.1	Q9NZN9-4

Frequencies

GnomAD3 genomes AF: 0.187 AC: 27366 AN: 146644 Hom.: 2803 Cov.: 30

Gnomad AFR AF: 0.0965

Gnomad AMI AF: 0.0902

Gnomad AMR AF: 0.213

Gnomad ASJ AF: 0.271

Gnomad EAS AF: 0.330

Gnomad SAS AF: 0.109

Gnomad FIN AF: 0.266

Gnomad MID AF: 0.361

Gnomad NFE AF: 0.207

Gnomad OTH AF: 0.234

GnomAD2 exomes AF: 0.209 AC: 52103 AN: 249150 AF XY: 0.204

Gnomad AFR exome AF: 0.0833

Gnomad AMR exome AF: 0.256

Gnomad ASJ exome AF: 0.293

Gnomad EAS exome AF: 0.328

Gnomad FIN exome AF: 0.248

Gnomad NFE exome AF: 0.204

Gnomad OTH exome AF: 0.223

GnomAD4 exome AF: 0.200 AC: 291904 AN: 1456726 Hom.: 30838 Cov.: 35 AF XY: 0.199 AC XY: 144384 AN XY: 724780

African (AFR) AF: 0.0863 AC: 2794 AN: 32360

American (AMR) AF: 0.249 AC: 11065 AN: 44454

Ashkenazi Jewish (ASJ) AF: 0.291 AC: 7611 AN: 26116

East Asian (EAS) AF: 0.355 AC: 14083 AN: 39646

South Asian (SAS) AF: 0.112 AC: 9681 AN: 86120

European-Finnish (FIN) AF: 0.242 AC: 12916 AN: 53320

Middle Eastern (MID) AF: 0.305 AC: 1714 AN: 5618

European-Non Finnish (NFE) AF: 0.198 AC: 219715 AN: 1109026

Other (OTH) AF: 0.205 AC: 12325 AN: 60066

GnomAD4 genome AF: 0.186 AC: 27356 AN: 146748 Hom.: 2802 Cov.: 30 AF XY: 0.188 AC XY: 13496 AN XY: 71810

African (AFR) AF: 0.0963 AC: 3583 AN: 37196

American (AMR) AF: 0.213 AC: 3201 AN: 15014

Ashkenazi Jewish (ASJ) AF: 0.271 AC: 940 AN: 3464

East Asian (EAS) AF: 0.329 AC: 1683 AN: 5120

South Asian (SAS) AF: 0.110 AC: 530 AN: 4806

European-Finnish (FIN) AF: 0.266 AC: 2802 AN: 10550

Middle Eastern (MID) AF: 0.354 AC: 104 AN: 294

European-Non Finnish (NFE) AF: 0.207 AC: 13959 AN: 67350

Other (OTH) AF: 0.230 AC: 473 AN: 2056

Alfa AF: 0.201 Hom.: 2693

Bravo AF: 0.178

TwinsUK AF: 0.186 AC: 688

ALSPAC AF: 0.192 AC: 740

ESP6500AA AF: 0.0869 AC: 383

ESP6500EA AF: 0.206 AC: 1768

ExAC AF: 0.200 AC: 24239

Asia WGS AF: 0.200 AC: 693 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (4)
-	-	2	Leber congenital amaurosis 4 (2)
-	-	1	AIPL1-related retinopathy (1)
-	-	1	Leber congenital amaurosis 1 (1)
-	-	1	not specified (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	Pathogenic	0.75
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Uncertain	0.040
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.37	T
Eigen	Benign	0.16
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.81	T
MetaRNN	Benign	0.0017	T
MetaSVM	Benign	-1.2	T
MutationAssessor	Benign	1.9	M
PhyloP100		4.7
PrimateAI	Uncertain	0.55	T
PROVEAN	Pathogenic	-5.6	D
REVEL	Uncertain	0.61
Sift	Benign	0.057	T
Sift4G	Uncertain	0.0070	D
Polyphen		0.71	P
Vest4		0.31
MPC		0.63
ClinPred		0.036	T
GERP RS		4.0
Varity_R		0.67
gMVP		0.84
Mutation Taster		=51/49	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: rs12449580; hg19: chr17-6337247; COSMIC: COSV51505907;