rs7984

Variant names:

• chr3-129528708-A-G
• rs7984
• NM_000539.3:c.-26A>G

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.-26A>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.216 in 1,613,362 control chromosomes in the GnomAD database, including 61,563 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.38 (17743 hom., cov: 32)
  • Exomes 𝑓: 0.20 (43820 hom.)
• Consequence: RHO NM_000539.3 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -1.33

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=-0.9).
• BP6: Variant 3-129528708-A-G is Benign according to our data. Variant chr3-129528708-A-G is described in ClinVar as [Benign]. Clinvar id is 256383.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-129528708-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.819 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RHO	NM_000539.3	c.-26A>G		5_prime_UTR_variant	Exon 1 of 5	ENST00000296271.4	NP_000530.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RHO	ENST00000296271	c.-26A>G		5_prime_UTR_variant	Exon 1 of 5	1	NM_000539.3	ENSP00000296271.3

Frequencies

GnomAD3 genomes AF: 0.378 AC: 57383 AN: 151928 Hom.: 17682 Cov.: 32

Gnomad AFR AF: 0.826

Gnomad AMI AF: 0.179

Gnomad AMR AF: 0.342

Gnomad ASJ AF: 0.286

Gnomad EAS AF: 0.633

Gnomad SAS AF: 0.383

Gnomad FIN AF: 0.0702

Gnomad MID AF: 0.287

Gnomad NFE AF: 0.150

Gnomad OTH AF: 0.344

GnomAD3 exomes AF: 0.277 AC: 69244 AN: 250244 Hom.: 15154 AF XY: 0.268 AC XY: 36285 AN XY: 135386

Gnomad AFR exome AF: 0.838

Gnomad AMR exome AF: 0.277

Gnomad ASJ exome AF: 0.276

Gnomad EAS exome AF: 0.637

Gnomad SAS exome AF: 0.379

Gnomad FIN exome AF: 0.0668

Gnomad NFE exome AF: 0.153

Gnomad OTH exome AF: 0.243

GnomAD4 exome AF: 0.200 AC: 291721 AN: 1461316 Hom.: 43820 Cov.: 33 AF XY: 0.204 AC XY: 148025 AN XY: 726934

Gnomad4 AFR exome AF: 0.853

Gnomad4 AMR exome AF: 0.281

Gnomad4 ASJ exome AF: 0.279

Gnomad4 EAS exome AF: 0.589

Gnomad4 SAS exome AF: 0.379

Gnomad4 FIN exome AF: 0.0703

Gnomad4 NFE exome AF: 0.150

Gnomad4 OTH exome AF: 0.255

GnomAD4 genome AF: 0.378 AC: 57507 AN: 152046 Hom.: 17743 Cov.: 32 AF XY: 0.378 AC XY: 28116 AN XY: 74330

Gnomad4 AFR AF: 0.826

Gnomad4 AMR AF: 0.342

Gnomad4 ASJ AF: 0.286

Gnomad4 EAS AF: 0.632

Gnomad4 SAS AF: 0.383

Gnomad4 FIN AF: 0.0702

Gnomad4 NFE AF: 0.150

Gnomad4 OTH AF: 0.345

Alfa AF: 0.279 Hom.: 2191

Bravo AF: 0.417

Asia WGS AF: 0.505 AC: 1760 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Pigmentary retinal dystrophy Benign:1

Nov 07, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Retinitis pigmentosa 4 Benign:1

Nov 07, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Congenital stationary night blindness autosomal dominant 1 Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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	-0.90
CADD	Benign	0.56
DANN	Benign	0.29

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: rs7984; hg19: chr3-129247551; COSMIC: COSV56214291;