rs151063543

Variant names:

• chr3-129530994-C-A
• rs151063543
• NM_000539.3:c.480C>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Moderate BP6 BP7 BS1 BS2

The NM_000539.3(RHO):​c.480C>A​(p.Thr160Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00235 in 1,614,244 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0017 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0024 (6 hom.)
• Consequence: RHO NM_000539.3 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:6
• Conservation: PhyloP100: 0.714
• Publications: 2 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: Labcorp Genetics (formerly Invitae), G2P
• inherited retinal dystrophy

  Inheritance: SD, AD Classification: DEFINITIVE Submitted by: ClinGen
• retinitis pigmentosa 4

  Inheritance: SD, AR, AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
• 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.27).
• BP6: Variant 3-129530994-C-A is Benign according to our data. Variant chr3-129530994-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 343277.
• BP7: Synonymous conserved (PhyloP=0.714 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00166 (253/152370) while in subpopulation NFE AF = 0.00266 (181/68034). AF 95% confidence interval is 0.00234. There are 1 homozygotes in GnomAd4. There are 117 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 6 AD,SD,Unknown,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000539.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RHO	NM_000539.3	MANE Select	c.480C>A	p.Thr160Thr	synonymous	Exon 2 of 5	NP_000530.1	P08100

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RHO	ENST00000296271.4	TSL:1 MANE Select	c.480C>A	p.Thr160Thr	synonymous	Exon 2 of 5	ENSP00000296271.3	P08100

Frequencies

GnomAD3 genomes AF: 0.00166 AC: 253 AN: 152252 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000627

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00164

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00179

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00266

Gnomad OTH AF: 0.000956

GnomAD2 exomes AF: 0.00152 AC: 383 AN: 251452 AF XY: 0.00151

Gnomad AFR exome AF: 0.000861

Gnomad AMR exome AF: 0.00199

Gnomad ASJ exome AF: 0.000198

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00125

Gnomad NFE exome AF: 0.00228

Gnomad OTH exome AF: 0.00196

GnomAD4 exome AF: 0.00242 AC: 3538 AN: 1461874 Hom.: 6 Cov.: 32 AF XY: 0.00238 AC XY: 1734 AN XY: 727242

African (AFR) AF: 0.000747 AC: 25 AN: 33480

American (AMR) AF: 0.00237 AC: 106 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000153 AC: 4 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.0000580 AC: 5 AN: 86258

European-Finnish (FIN) AF: 0.00124 AC: 66 AN: 53400

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5768

European-Non Finnish (NFE) AF: 0.00288 AC: 3206 AN: 1112012

Other (OTH) AF: 0.00202 AC: 122 AN: 60396

GnomAD4 genome AF: 0.00166 AC: 253 AN: 152370 Hom.: 1 Cov.: 33 AF XY: 0.00157 AC XY: 117 AN XY: 74518

African (AFR) AF: 0.000625 AC: 26 AN: 41592

American (AMR) AF: 0.00163 AC: 25 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00179 AC: 19 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00266 AC: 181 AN: 68034

Other (OTH) AF: 0.000946 AC: 2 AN: 2114

Alfa AF: 0.00251 Hom.: 1

Bravo AF: 0.00175

EpiCase AF: 0.00338

EpiControl AF: 0.00267

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	3	not provided (4)
-	-	1	Congenital stationary night blindness autosomal dominant 1 (1)
-	-	1	not specified (1)
-	-	1	Retinitis pigmentosa (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.27
CADD	Benign	7.7
DANN	Benign	0.61
PhyloP100		0.71
Mutation Taster		=92/8	polymorphism

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: rs151063543; hg19: chr3-129249837;