1-211476533-C-A

Position:

• chr1-211476533-C-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001164688.2(RD3):​c.*2503G>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0345 in 152,176 control chromosomes in the GnomAD database, including 132 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.034 (132 hom., cov: 31)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: RD3 NM_001164688.2 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.546

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.62).
• BP6: Variant 1-211476533-C-A is Benign according to our data. Variant chr1-211476533-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 295220.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0516 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RD3	NM_001164688.2	c.*2503G>T		3_prime_UTR_variant	3/3	ENST00000680073.1
RD3	NM_183059.3	c.*2503G>T		3_prime_UTR_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RD3	ENST00000680073.1	c.*2503G>T		3_prime_UTR_variant	3/3		NM_001164688.2	P1
RD3	ENST00000367002.5	c.*2503G>T		3_prime_UTR_variant	3/3	1		P1
RD3	ENST00000484910.1	n.3059G>T		non_coding_transcript_exon_variant	2/2	1

Frequencies

GnomAD3 genomes AF: 0.0345 AC: 5252 AN: 152058 Hom.: 132 Cov.: 31

Gnomad AFR AF: 0.00882

Gnomad AMI AF: 0.133

Gnomad AMR AF: 0.0383

Gnomad ASJ AF: 0.0698

Gnomad EAS AF: 0.0429

Gnomad SAS AF: 0.0567

Gnomad FIN AF: 0.0166

Gnomad MID AF: 0.120

Gnomad NFE AF: 0.0462

Gnomad OTH AF: 0.0421

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 4 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 4

Gnomad4 NFE exome AF: 0.00

GnomAD4 genome AF: 0.0345 AC: 5248 AN: 152176 Hom.: 132 Cov.: 31 AF XY: 0.0340 AC XY: 2526 AN XY: 74390

Gnomad4 AFR AF: 0.00881

Gnomad4 AMR AF: 0.0382

Gnomad4 ASJ AF: 0.0698

Gnomad4 EAS AF: 0.0428

Gnomad4 SAS AF: 0.0571

Gnomad4 FIN AF: 0.0166

Gnomad4 NFE AF: 0.0462

Gnomad4 OTH AF: 0.0412

Alfa AF: 0.0363 Hom.: 14

Bravo AF: 0.0342

Asia WGS AF: 0.0600 AC: 210 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Leber congenital amaurosis 12 Benign:1

Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.62
CADD	Benign	11
DANN	Benign	0.79

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: rs41309617; hg19: chr1-211649875;