rs786205148

Positions:

• chr1-211481304-G-A

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The NM_001164688.2(RD3):​c.112C>T​(p.Arg38Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000821 in 1,461,870 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000082 (0 hom.)
• Consequence: RD3 NM_001164688.2 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 4.10

Genes affected

RD3 (HGNC:19689): (RD3 regulator of GUCY2D) This gene encodes a retinal protein that is associated with promyelocytic leukemia-gene product (PML) bodies in the nucleus. Mutations in this gene cause Leber congenital amaurosis type 12, a disease that results in retinal degeneration. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Sep 2009]

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 6 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-211481304-G-A is Pathogenic according to our data. Variant chr1-211481304-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 189792.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-211481304-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RD3	NM_001164688.2	c.112C>T	p.Arg38Ter	stop_gained	2/3	ENST00000680073.1	NP_001158160.1
RD3	NM_183059.3	c.112C>T	p.Arg38Ter	stop_gained	2/3		NP_898882.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RD3	ENST00000680073.1	c.112C>T	p.Arg38Ter	stop_gained	2/3		NM_001164688.2	ENSP00000505312	P1
RD3	ENST00000367002.5	c.112C>T	p.Arg38Ter	stop_gained	2/3	1		ENSP00000355969	P1
RD3	ENST00000484910.1	n.265-1977C>T		intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251300 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135828

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000821 AC: 12 AN: 1461870 Hom.: 0 Cov.: 32 AF XY: 0.00000688 AC XY: 5 AN XY: 727242

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000809

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000508 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Leber congenital amaurosis 12 Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 27, 2023	This sequence change creates a premature translational stop signal (p.Arg38*) in the RD3 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in RD3 are known to be pathogenic (PMID: 23308101). This variant is present in population databases (rs786205148, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with Leber congenital amaurosis (PMID: 23308101). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 189792). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 2013	- -
Pathogenic, no assertion criteria provided	research	Laboratory of Genetics in Ophthalmology, Institut Imagine	-	- -

RD3-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 22, 2023

The RD3 c.112C>T variant is predicted to result in premature protein termination (p.Arg38*). This variant has been reported in the homozygous state multiple individuals with Leber congenital amaurosis (Perrault et al 2013. PubMed ID: 23308101; Table S1, Weisschuh et al. 2020. PubMed ID: 32531858). This variant is reported in 0.00088% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Nonsense variants in RD3 are expected to be pathogenic. Given all the evidence, we interpret this variant as pathogenic. -

Abnormality of the eye Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Kariminejad - Najmabadi Pathology & Genetics Center

Jul 10, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	40
DANN	Uncertain	1.0
Eigen	Pathogenic	0.69
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Uncertain	0.86	D
MutationTaster	Benign	1.0	A
Vest4		0.38
GERP RS		1.1

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

Publications

LitVar

Other links and lift over

dbSNP: rs786205148; hg19: chr1-211654646; COSMIC: COSV65362080;