NM_000539.3:c.696+4C>T

Variant names:

• chr3-129532420-C-T
• rs56340615
• NM_000539.3:c.696+4C>T

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.696+4C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0847 in 1,613,784 control chromosomes in the GnomAD database, including 6,274 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.078 (525 hom., cov: 32)
  • Exomes 𝑓: 0.085 (5749 hom.)
• Consequence: RHO NM_000539.3 splice_region, intron
• Scores: Splicing: ADA: 0.00009567
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -5.24
• 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: 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 3-129532420-C-T is Benign according to our data. Variant chr3-129532420-C-T is described in ClinVar as Benign. ClinVar VariationId is 256384.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.101 is higher than 0.05.

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.696+4C>T		splice_region intron	N/A	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.696+4C>T		splice_region intron	N/A	ENSP00000296271.3	P08100

Frequencies

GnomAD3 genomes AF: 0.0780 AC: 11858 AN: 151988 Hom.: 524 Cov.: 32

Gnomad AFR AF: 0.0698

Gnomad AMI AF: 0.0307

Gnomad AMR AF: 0.0802

Gnomad ASJ AF: 0.161

Gnomad EAS AF: 0.0639

Gnomad SAS AF: 0.108

Gnomad FIN AF: 0.0374

Gnomad MID AF: 0.0949

Gnomad NFE AF: 0.0836

Gnomad OTH AF: 0.0946

GnomAD2 exomes AF: 0.0815 AC: 20448 AN: 250880 AF XY: 0.0854

Gnomad AFR exome AF: 0.0716

Gnomad AMR exome AF: 0.0600

Gnomad ASJ exome AF: 0.163

Gnomad EAS exome AF: 0.0634

Gnomad FIN exome AF: 0.0360

Gnomad NFE exome AF: 0.0837

Gnomad OTH exome AF: 0.101

GnomAD4 exome AF: 0.0854 AC: 124825 AN: 1461678 Hom.: 5749 Cov.: 34 AF XY: 0.0873 AC XY: 63481 AN XY: 727136

African (AFR) AF: 0.0691 AC: 2315 AN: 33480

American (AMR) AF: 0.0621 AC: 2777 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.163 AC: 4267 AN: 26136

East Asian (EAS) AF: 0.0510 AC: 2025 AN: 39700

South Asian (SAS) AF: 0.118 AC: 10151 AN: 86258

European-Finnish (FIN) AF: 0.0379 AC: 2018 AN: 53266

Middle Eastern (MID) AF: 0.128 AC: 736 AN: 5768

European-Non Finnish (NFE) AF: 0.0853 AC: 94889 AN: 1111962

Other (OTH) AF: 0.0935 AC: 5647 AN: 60384

GnomAD4 genome AF: 0.0781 AC: 11874 AN: 152106 Hom.: 525 Cov.: 32 AF XY: 0.0776 AC XY: 5770 AN XY: 74370

African (AFR) AF: 0.0700 AC: 2905 AN: 41500

American (AMR) AF: 0.0801 AC: 1225 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.161 AC: 560 AN: 3468

East Asian (EAS) AF: 0.0635 AC: 327 AN: 5152

South Asian (SAS) AF: 0.108 AC: 522 AN: 4822

European-Finnish (FIN) AF: 0.0374 AC: 396 AN: 10590

Middle Eastern (MID) AF: 0.0918 AC: 27 AN: 294

European-Non Finnish (NFE) AF: 0.0836 AC: 5682 AN: 67968

Other (OTH) AF: 0.0956 AC: 202 AN: 2114

Alfa AF: 0.0839 Hom.: 396

Bravo AF: 0.0802

Asia WGS AF: 0.106 AC: 372 AN: 3478

EpiCase AF: 0.0953

EpiControl AF: 0.0969

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.0020
DANN	Benign	0.64
PhyloP100		-5.2
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000096
dbscSNV1_RF	Benign	0.0020
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: rs56340615; hg19: chr3-129251263; COSMIC: COSV56214717;