3-129533710-C-A

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1PM2PM5PP3_StrongPP5_Moderate

The NM_000539.3(RHO):​c.1039C>A​(p.Pro347Thr) 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. P347L) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Consequence

RHO
NM_000539.3 missense

Scores

6
7
6

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 5.46
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PM1
In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 4 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 chr3-129533711-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 13014.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.955
PP5
Variant 3-129533710-C-A is Pathogenic according to our data. Variant chr3-129533710-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 1070044.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr3-129533710-C-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
RHONM_000539.3 linkuse as main transcriptc.1039C>A p.Pro347Thr missense_variant 5/5 ENST00000296271.4

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
RHOENST00000296271.4 linkuse as main transcriptc.1039C>A p.Pro347Thr missense_variant 5/51 NM_000539.3 P1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not provided Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingInvitaeSep 11, 2020This sequence change replaces proline with threonine at codon 347 of the RHO protein (p.Pro347Thr). The proline residue is highly conserved and there is a small physicochemical difference between proline and threonine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with autosomal dominant retinitis pigmentosa (PMID: 11139241, 26202387, 10967073). 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. This variant disrupts the p.Pro347 amino acid residue in RHO. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 2215617, 25221422). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.13
BayesDel_addAF
Pathogenic
0.31
D
BayesDel_noAF
Pathogenic
0.21
CADD
Uncertain
24
DANN
Uncertain
0.99
DEOGEN2
Uncertain
0.72
D
Eigen
Pathogenic
0.68
Eigen_PC
Pathogenic
0.67
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Benign
0.85
T
M_CAP
Uncertain
0.14
D
MetaRNN
Pathogenic
0.95
D
MetaSVM
Uncertain
-0.10
T
MutationAssessor
Benign
1.1
L
MutationTaster
Benign
1.0
D
PrimateAI
Uncertain
0.61
T
PROVEAN
Benign
-2.2
N
REVEL
Uncertain
0.44
Sift
Pathogenic
0.0
D
Sift4G
Benign
0.070
T
Polyphen
1.0
D
Vest4
0.89
MutPred
0.83
Gain of glycosylation at T342 (P = 0.0733);
MVP
0.92
MPC
0.87
ClinPred
0.90
D
GERP RS
5.4
Varity_R
0.58
gMVP
0.86

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr3-129252553; API