rs2269736

chr3-129528683-G-Achr3-129528683-G-C

Variant summary

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

The NM_000539.3(RHO):c.-51G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.03 in 1,612,158 control chromosomes in the GnomAD database, including 5,409 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.084 (1361 hom., cov: 33)
  • Exomes 𝑓: 0.024 (4048 hom.)
• Consequence: RHO NM_000539.3 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.38

Genes affected

RHO (HGNC:10012): (rhodopsin) The protein encoded by this gene is found in rod cells in the back of the eye and is essential for vision in low-light conditions. The encoded protein binds to 11-cis retinal and is activated when light hits the retinal molecule. Defects in this gene are a cause of congenital stationary night blindness. [provided by RefSeq, Aug 2017]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.64).
• BP6: Variant 3-129528683-G-A is Benign according to our data. Variant chr3-129528683-G-A is described in ClinVar as [Benign]. Clinvar id is 343272.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.388 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RHO	NM_000539.3	c.-51G>A		5_prime_UTR_variant	1/5	ENST00000296271.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RHO	ENST00000296271.4	c.-51G>A		5_prime_UTR_variant	1/5	1	NM_000539.3	P1

Frequencies

GnomAD3 genomes AF: 0.0837 AC: 12729 AN: 152088 Hom.: 1359 Cov.: 33

Gnomad AFR AF: 0.186

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.153

Gnomad ASJ AF: 0.00836

Gnomad EAS AF: 0.403

Gnomad SAS AF: 0.0321

Gnomad FIN AF: 0.00358

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00363

Gnomad OTH AF: 0.0693

GnomAD3 exomes AF: 0.0701 AC: 17360 AN: 247792 Hom.: 2319 AF XY: 0.0596 AC XY: 8011 AN XY: 134456

Gnomad AFR exome AF: 0.187

Gnomad AMR exome AF: 0.164

Gnomad ASJ exome AF: 0.00549

Gnomad EAS exome AF: 0.404

Gnomad SAS exome AF: 0.0217

Gnomad FIN exome AF: 0.00361

Gnomad NFE exome AF: 0.00385

Gnomad OTH exome AF: 0.0437

GnomAD4 exome AF: 0.0243 AC: 35534 AN: 1459952 Hom.: 4048 Cov.: 31 AF XY: 0.0229 AC XY: 16630 AN XY: 726300

Gnomad4 AFR exome AF: 0.184

Gnomad4 AMR exome AF: 0.160

Gnomad4 ASJ exome AF: 0.00632

Gnomad4 EAS exome AF: 0.357

Gnomad4 SAS exome AF: 0.0223

Gnomad4 FIN exome AF: 0.00331

Gnomad4 NFE exome AF: 0.00280

Gnomad4 OTH exome AF: 0.0441

GnomAD4 genome AF: 0.0839 AC: 12771 AN: 152206 Hom.: 1361 Cov.: 33 AF XY: 0.0871 AC XY: 6479 AN XY: 74418

Gnomad4 AFR AF: 0.186

Gnomad4 AMR AF: 0.154

Gnomad4 ASJ AF: 0.00836

Gnomad4 EAS AF: 0.402

Gnomad4 SAS AF: 0.0320

Gnomad4 FIN AF: 0.00358

Gnomad4 NFE AF: 0.00363

Gnomad4 OTH AF: 0.0695

Alfa AF: 0.0166 Hom.: 165

Bravo AF: 0.101

Asia WGS AF: 0.176 AC: 611 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

Congenital stationary night blindness autosomal dominant 1 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. -

Retinitis pigmentosa 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	-0.64
Cadd	Benign	9.9
Dann	Benign	0.80

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: rs2269736; hg19: chr3-129247526; COSMIC: COSV56213998;