1-211481236-G-T

Position:

• chr1-211481236-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_Strong PM2 PP5_Moderate

The NM_001164688.2(RD3):​c.180C>A​(p.Tyr60*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: RD3 NM_001164688.2 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 2.93

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]

RD3 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 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 1-211481236-G-T is Pathogenic according to our data. Variant chr1-211481236-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 189791.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-211481236-G-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RD3	NM_001164688.2	c.180C>A	p.Tyr60*	stop_gained	2/3	ENST00000680073.1	NP_001158160.1
RD3	NM_183059.3	c.180C>A	p.Tyr60*	stop_gained	2/3		NP_898882.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RD3	ENST00000680073.1	c.180C>A	p.Tyr60*	stop_gained	2/3		NM_001164688.2	ENSP00000505312.1
RD3	ENST00000367002.5	c.180C>A	p.Tyr60*	stop_gained	2/3	1		ENSP00000355969.4
RD3	ENST00000484910.1	n.265-1909C>A		intron_variant		1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Leber congenital amaurosis 12 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jun 08, 2012

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jul 01, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.63
CADD	Pathogenic	37
DANN	Uncertain	1.0
Eigen	Pathogenic	0.73
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Uncertain	0.94	D
Vest4		0.70
GERP RS		3.9

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs762631020; hg19: chr1-211654578;