rs104893793

chr3-129531005-C-Achr3-129531005-C-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Moderate

The NM_000539.3(RHO):c.491C>A(p.Ala164Glu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A164V) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: RHO NM_000539.3 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 6.08

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 Pathogenic. Variant got 12 ACMG points.

• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 6 uncertain in NM_000539.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr3-129531005-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 417867.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.991
• PP5: Variant 3-129531005-C-A is Pathogenic according to our data. Variant chr3-129531005-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 13049.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr3-129531005-C-A is described in Lovd as [Pathogenic]. Variant chr3-129531005-C-A is described in Lovd as [Pathogenic]. Variant chr3-129531005-C-A is described in Lovd as [Likely_pathogenic]. Variant chr3-129531005-C-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RHO	NM_000539.3	c.491C>A	p.Ala164Glu	missense_variant	2/5	ENST00000296271.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RHO	ENST00000296271.4	c.491C>A	p.Ala164Glu	missense_variant	2/5	1	NM_000539.3	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Retinitis pigmentosa 4 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

May 15, 1994

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Oct 05, 2022

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Ala164 amino acid residue in RHO. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7981701, 9380676, 11139241, 17488458). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt RHO protein function. ClinVar contains an entry for this variant (Variation ID: 13049). This missense change has been observed in individuals with autosomal dominant retinitis pigmentosa (PMID: 8088850, 29847639). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 164 of the RHO protein (p.Ala164Glu). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.20
Cadd	Pathogenic	27
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.88	D
Eigen	Pathogenic	0.92
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Uncertain	0.23	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Uncertain	0.27	D
MutationAssessor	Pathogenic	4.2	H
MutationTaster	Benign	1.0	A
PrimateAI	Uncertain	0.76	T
PROVEAN	Uncertain	-3.4	D
REVEL	Uncertain	0.55
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.95
MutPred		0.95		Loss of catalytic residue at C167 (P = 0.0952);
MVP		0.95
MPC		0.94
ClinPred		1.0	D
GERP RS		5.3
Varity_R		0.98
gMVP		0.99

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: rs104893793; hg19: chr3-129249848;