1-211477387-A-G

Position:

• chr1-211477387-A-G

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.*1649T>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 0.186 in 151,630 control chromosomes in the GnomAD database, including 3,407 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.19 (3407 hom., cov: 30)
  • Exomes 𝑓: 0.091 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: RD3 NM_001164688.2 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.799

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=-1.01).
• BP6: Variant 1-211477387-A-G is Benign according to our data. Variant chr1-211477387-A-G is described in ClinVar as [Benign]. Clinvar id is 295231.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.323 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RD3	NM_001164688.2	c.*1649T>C		3_prime_UTR_variant	3/3	ENST00000680073.1	NP_001158160.1
RD3	NM_183059.3	c.*1649T>C		3_prime_UTR_variant	3/3		NP_898882.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RD3	ENST00000680073.1	c.*1649T>C		3_prime_UTR_variant	3/3		NM_001164688.2	ENSP00000505312	P1
RD3	ENST00000367002.5	c.*1649T>C		3_prime_UTR_variant	3/3	1		ENSP00000355969	P1
RD3	ENST00000484910.1	n.2205T>C		non_coding_transcript_exon_variant	2/2	1

Frequencies

GnomAD3 genomes AF: 0.186 AC: 28221 AN: 151512 Hom.: 3399 Cov.: 30

Gnomad AFR AF: 0.327

Gnomad AMI AF: 0.117

Gnomad AMR AF: 0.194

Gnomad ASJ AF: 0.154

Gnomad EAS AF: 0.312

Gnomad SAS AF: 0.141

Gnomad FIN AF: 0.0879

Gnomad MID AF: 0.133

Gnomad NFE AF: 0.111

Gnomad OTH AF: 0.172

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0909 AC: 2 AN: 22 Hom.: 0 Cov.: 0 AF XY: 0.100 AC XY: 2 AN XY: 20

Gnomad4 AMR exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.125

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.186 AC: 28257 AN: 151630 Hom.: 3407 Cov.: 30 AF XY: 0.186 AC XY: 13773 AN XY: 74128

Gnomad4 AFR AF: 0.327

Gnomad4 AMR AF: 0.195

Gnomad4 ASJ AF: 0.154

Gnomad4 EAS AF: 0.311

Gnomad4 SAS AF: 0.140

Gnomad4 FIN AF: 0.0879

Gnomad4 NFE AF: 0.111

Gnomad4 OTH AF: 0.171

Alfa AF: 0.142 Hom.: 267

Bravo AF: 0.200

Asia WGS AF: 0.228 AC: 792 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

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. -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	1.5
DANN	Benign	0.37

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: rs12076715; hg19: chr1-211650729;