3-129528683-G-A

Variant names:

• chr3-129528683-G-A
• rs2269736
• NM_000539.3:c.-51G>A

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.-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:4
• Conservation: PhyloP100: 1.38
• Publications: 8 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=-0.64).
• 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 rank	MANE	Protein	UniProt
RHO	NM_000539.3	c.-51G>A		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.-51G>A		5_prime_UTR_variant	Exon 1 of 5	1	NM_000539.3	ENSP00000296271.3

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

GnomAD2 exomes AF: 0.0701 AC: 17360 AN: 247792 AF XY: 0.0596

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 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

African (AFR) AF: 0.184 AC: 6140 AN: 33396

American (AMR) AF: 0.160 AC: 7129 AN: 44592

Ashkenazi Jewish (ASJ) AF: 0.00632 AC: 165 AN: 26120

East Asian (EAS) AF: 0.357 AC: 14142 AN: 39614

South Asian (SAS) AF: 0.0223 AC: 1922 AN: 86010

European-Finnish (FIN) AF: 0.00331 AC: 175 AN: 52822

Middle Eastern (MID) AF: 0.0171 AC: 91 AN: 5318

European-Non Finnish (NFE) AF: 0.00280 AC: 3109 AN: 1111794

Other (OTH) AF: 0.0441 AC: 2661 AN: 60286

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

African (AFR) AF: 0.186 AC: 7725 AN: 41506

American (AMR) AF: 0.154 AC: 2353 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00836 AC: 29 AN: 3468

East Asian (EAS) AF: 0.402 AC: 2076 AN: 5164

South Asian (SAS) AF: 0.0320 AC: 154 AN: 4820

European-Finnish (FIN) AF: 0.00358 AC: 38 AN: 10622

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00363 AC: 247 AN: 68016

Other (OTH) AF: 0.0695 AC: 147 AN: 2114

Alfa AF: 0.0278 Hom.: 416

Bravo AF: 0.101

Asia WGS AF: 0.176 AC: 611 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

- -

Congenital stationary night blindness autosomal dominant 1 Benign:1

Jan 13, 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 13, 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	-0.64
CADD	Benign	9.9
DANN	Benign	0.80
PhyloP100		1.4
PromoterAI		-0.024	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: rs2269736; hg19: chr3-129247526; COSMIC: COSV56213998;