rs150427474

Variant names:

• chr17-6425644-C-A
• rs150427474
• NM_014336.5:c.971G>T

Your query was ambiguous. Multiple possible variants found:

• chr17-6425644-C-A
• chr17-6425644-C-G
• chr17-6425644-C-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_014336.5(AIPL1):​c.971G>T​(p.Arg324Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00552 in 1,612,140 control chromosomes in the GnomAD database, including 21 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★). Synonymous variant affecting the same amino acid position (i.e. R324R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0035 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0057 (21 hom.)
• Consequence: AIPL1 NM_014336.5 missense
• Clinical Significance: Benign reviewed by expert panel U:5 B:5
• Conservation: PhyloP100: 1.90
• Publications: 7 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=0.020529807).
• BP6: Variant 17-6425644-C-A is Benign according to our data. Variant chr17-6425644-C-A is described in ClinVar as Benign. ClinVar VariationId is 198208.Status of the report is reviewed_by_expert_panel, 3 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00349 (532/152232) while in subpopulation NFE AF = 0.00621 (422/67990). AF 95% confidence interval is 0.00572. There are 0 homozygotes in GnomAd4. There are 245 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 21 AR,AD gene

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.971G>T	p.Arg324Leu	missense	Exon 6 of 6	NP_055151.3
	AIPL1	NM_001285399.3		c.935G>T	p.Arg312Leu	missense	Exon 6 of 6	NP_001272328.1	Q7Z3H1
	AIPL1	NM_001285400.3		c.905G>T	p.Arg302Leu	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.971G>T	p.Arg324Leu	missense	Exon 6 of 6	ENSP00000370521.3	Q9NZN9-1
	AIPL1	ENST00000574506.5	TSL:1	c.935G>T	p.Arg312Leu	missense	Exon 6 of 6	ENSP00000458456.1	Q7Z3H1
	AIPL1	ENST00000570466.5	TSL:1	c.905G>T	p.Arg302Leu	missense	Exon 6 of 6	ENSP00000461287.1	Q9NZN9-4

Frequencies

GnomAD3 genomes AF: 0.00350 AC: 532 AN: 152114 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00135

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.00203

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00621

Gnomad OTH AF: 0.00478

GnomAD2 exomes AF: 0.00384 AC: 953 AN: 248490 AF XY: 0.00386

Gnomad AFR exome AF: 0.000926

Gnomad AMR exome AF: 0.00315

Gnomad ASJ exome AF: 0.0000994

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000693

Gnomad NFE exome AF: 0.00632

Gnomad OTH exome AF: 0.00377

GnomAD4 exome AF: 0.00573 AC: 8360 AN: 1459908 Hom.: 21 Cov.: 32 AF XY: 0.00565 AC XY: 4102 AN XY: 726368

African (AFR) AF: 0.000896 AC: 30 AN: 33474

American (AMR) AF: 0.00327 AC: 146 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.000191 AC: 5 AN: 26120

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00218 AC: 188 AN: 86246

European-Finnish (FIN) AF: 0.000987 AC: 51 AN: 51652

Middle Eastern (MID) AF: 0.000871 AC: 5 AN: 5740

European-Non Finnish (NFE) AF: 0.00686 AC: 7631 AN: 1111906

Other (OTH) AF: 0.00504 AC: 304 AN: 60358

GnomAD4 genome AF: 0.00349 AC: 532 AN: 152232 Hom.: 0 Cov.: 32 AF XY: 0.00329 AC XY: 245 AN XY: 74418

African (AFR) AF: 0.00135 AC: 56 AN: 41540

American (AMR) AF: 0.00203 AC: 31 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00166 AC: 8 AN: 4822

European-Finnish (FIN) AF: 0.000283 AC: 3 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00621 AC: 422 AN: 67990

Other (OTH) AF: 0.00473 AC: 10 AN: 2114

Alfa AF: 0.00534 Hom.: 6

Bravo AF: 0.00377

TwinsUK AF: 0.00485 AC: 18

ALSPAC AF: 0.00675 AC: 26

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00651 AC: 56

ExAC AF: 0.00383 AC: 465

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00703

EpiControl AF: 0.00747

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.35
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Uncertain	-0.070
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.28	T
Eigen	Benign	-0.28
Eigen_PC	Benign	-0.24
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.80	T
M_CAP	Pathogenic	0.61	D
MetaRNN	Benign	0.021	T
MetaSVM	Uncertain	-0.18	T
MutationAssessor	Benign	0.55	N
PhyloP100		1.9
PrimateAI	Benign	0.36	T
PROVEAN	Uncertain	-3.1	D
REVEL	Uncertain	0.40
Sift	Uncertain	0.023	D
Sift4G	Benign	0.073	T
Polyphen		0.65	P
Vest4		0.23
MVP		0.94
MPC		0.33
ClinPred		0.048	T
GERP RS		2.7
Varity_R		0.15
gMVP		0.51
Mutation Taster		=68/32	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: rs150427474; hg19: chr17-6328964; COSMIC: COSV106084708; COSMIC: COSV106084708;