1-211477693-C-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001164688.2(RD3):c.*1343G>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.181 in 161,090 control chromosomes in the GnomAD database, including 3,401 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.18 (3308 hom., cov: 32)
  • Exomes 𝑓: 0.12 (93 hom.)
• Consequence: RD3 NM_001164688.2 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.219

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 Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 1-211477693-C-G is Benign according to our data. Variant chr1-211477693-C-G is described in ClinVar as [Benign]. Clinvar id is 295237.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.317 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RD3	NM_001164688.2	c.*1343G>C		3_prime_UTR_variant	3/3	ENST00000680073.1
RD3	NM_183059.3	c.*1343G>C		3_prime_UTR_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RD3	ENST00000680073.1	c.*1343G>C		3_prime_UTR_variant	3/3		NM_001164688.2	P1
RD3	ENST00000367002.5	c.*1343G>C		3_prime_UTR_variant	3/3	1		P1
RD3	ENST00000484910.1	n.1899G>C		non_coding_transcript_exon_variant	2/2	1

Frequencies

GnomAD3 genomes AF: 0.185 AC: 28034 AN: 151926 Hom.: 3300 Cov.: 32

Gnomad AFR AF: 0.321

Gnomad AMI AF: 0.115

Gnomad AMR AF: 0.194

Gnomad ASJ AF: 0.153

Gnomad EAS AF: 0.309

Gnomad SAS AF: 0.142

Gnomad FIN AF: 0.0891

Gnomad MID AF: 0.133

Gnomad NFE AF: 0.111

Gnomad OTH AF: 0.169

GnomAD4 exome AF: 0.118 AC: 1071 AN: 9046 Hom.: 93 Cov.: 0 AF XY: 0.116 AC XY: 540 AN XY: 4656

Gnomad4 AFR exome AF: 0.252

Gnomad4 AMR exome AF: 0.182

Gnomad4 ASJ exome AF: 0.167

Gnomad4 EAS exome AF: 0.219

Gnomad4 SAS exome AF: 0.125

Gnomad4 FIN exome AF: 0.0670

Gnomad4 NFE exome AF: 0.0989

Gnomad4 OTH exome AF: 0.150

GnomAD4 genome AF: 0.185 AC: 28069 AN: 152044 Hom.: 3308 Cov.: 32 AF XY: 0.184 AC XY: 13682 AN XY: 74330

Gnomad4 AFR AF: 0.321

Gnomad4 AMR AF: 0.194

Gnomad4 ASJ AF: 0.153

Gnomad4 EAS AF: 0.308

Gnomad4 SAS AF: 0.141

Gnomad4 FIN AF: 0.0891

Gnomad4 NFE AF: 0.111

Gnomad4 OTH AF: 0.168

Alfa AF: 0.149 Hom.: 310

Bravo AF: 0.198

Asia WGS AF: 0.228 AC: 791 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Leber congenital amaurosis 12 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
Cadd	Benign	2.9
Dann	Benign	0.70

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: rs11119746; hg19: chr1-211651035;