rs2410

Positions:

• chr3-129533950-A-G
• chr3-129533950-A-T

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.*232A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0941 in 497,922 control chromosomes in the GnomAD database, including 7,903 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.13 (3249 hom., cov: 32)
  • Exomes 𝑓: 0.077 (4654 hom.)
• Consequence: RHO NM_000539.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.780

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=-0.8).
• BP6: Variant 3-129533950-A-G is Benign according to our data. Variant chr3-129533950-A-G is described in ClinVar as [Benign]. Clinvar id is 343290.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.533 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RHO	NM_000539.3	c.*232A>G		3_prime_UTR_variant	5/5	ENST00000296271.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RHO	ENST00000296271.4	c.*232A>G		3_prime_UTR_variant	5/5	1	NM_000539.3	P1

Frequencies

GnomAD3 genomes AF: 0.132 AC: 20015 AN: 151520 Hom.: 3239 Cov.: 32

Gnomad AFR AF: 0.318

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.168

Gnomad ASJ AF: 0.00866

Gnomad EAS AF: 0.550

Gnomad SAS AF: 0.160

Gnomad FIN AF: 0.0103

Gnomad MID AF: 0.0191

Gnomad NFE AF: 0.00614

Gnomad OTH AF: 0.104

GnomAD4 exome AF: 0.0773 AC: 26775 AN: 346286 Hom.: 4654 Cov.: 0 AF XY: 0.0797 AC XY: 14470 AN XY: 181548

Gnomad4 AFR exome AF: 0.313

Gnomad4 AMR exome AF: 0.161

Gnomad4 ASJ exome AF: 0.00815

Gnomad4 EAS exome AF: 0.528

Gnomad4 SAS exome AF: 0.143

Gnomad4 FIN exome AF: 0.00916

Gnomad4 NFE exome AF: 0.00634

Gnomad4 OTH exome AF: 0.0732

GnomAD4 genome AF: 0.132 AC: 20065 AN: 151636 Hom.: 3249 Cov.: 32 AF XY: 0.137 AC XY: 10163 AN XY: 74094

Gnomad4 AFR AF: 0.318

Gnomad4 AMR AF: 0.169

Gnomad4 ASJ AF: 0.00866

Gnomad4 EAS AF: 0.550

Gnomad4 SAS AF: 0.159

Gnomad4 FIN AF: 0.0103

Gnomad4 NFE AF: 0.00614

Gnomad4 OTH AF: 0.104

Alfa AF: 0.0702 Hom.: 510

Bravo AF: 0.152

Asia WGS AF: 0.315 AC: 1095 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

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Congenital stationary night blindness autosomal dominant 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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 12, 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	-0.80
CADD	Benign	8.9
DANN	Benign	0.57

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: rs2410; hg19: chr3-129252793; COSMIC: COSV56215006;