rs7984

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 20 publications found

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]

RHO Gene-Disease associations (from GenCC):

• congenital stationary night blindness autosomal dominant 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• retinitis pigmentosa 4

  Inheritance: AD, AR, SD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• congenital stationary night blindness

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• retinitis pigmentosa

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• fundus albipunctatus

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -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.
• 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	ENST00000296271.4	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

GnomAD2 exomes AF: 0.277 AC: 69244 AN: 250244 AF XY: 0.268

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 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

African (AFR) AF: 0.853 AC: 28533 AN: 33458

American (AMR) AF: 0.281 AC: 12539 AN: 44678

Ashkenazi Jewish (ASJ) AF: 0.279 AC: 7290 AN: 26134

East Asian (EAS) AF: 0.589 AC: 23357 AN: 39684

South Asian (SAS) AF: 0.379 AC: 32696 AN: 86218

European-Finnish (FIN) AF: 0.0703 AC: 3747 AN: 53304

Middle Eastern (MID) AF: 0.301 AC: 1709 AN: 5676

European-Non Finnish (NFE) AF: 0.150 AC: 166486 AN: 1111804

Other (OTH) AF: 0.255 AC: 15364 AN: 60360

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

African (AFR) AF: 0.826 AC: 34264 AN: 41468

American (AMR) AF: 0.342 AC: 5229 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.286 AC: 991 AN: 3468

East Asian (EAS) AF: 0.632 AC: 3254 AN: 5146

South Asian (SAS) AF: 0.383 AC: 1840 AN: 4810

European-Finnish (FIN) AF: 0.0702 AC: 744 AN: 10600

Middle Eastern (MID) AF: 0.274 AC: 80 AN: 292

European-Non Finnish (NFE) AF: 0.150 AC: 10215 AN: 67976

Other (OTH) AF: 0.345 AC: 727 AN: 2106

Alfa AF: 0.431 Hom.: 6541

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

- -

-

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

Significance: Benign

Review Status: no assertion criteria provided

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

- -

not provided Benign:2

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

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
PhyloP100		-1.3
PromoterAI		0.0094	Neutral
Mutation Taster		=300/0	polymorphism (auto)

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

Other links and lift over

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