chr3-129528778-T-A

Variant summary

Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PS1_Very_StrongPM1PM2PM5PP3_StrongPP5_Moderate

The NM_000539.3(RHO):​c.45T>A​(p.Asn15Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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 Likely pathogenic (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N15S) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 33)

Consequence

RHO
NM_000539.3 missense

Scores

11
4
4

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 0.787
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 20 ACMG points.

PS1
Transcript NM_000539.3 (RHO) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar as 802004
PM1
In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 10 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 chr3-129528777-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 13042.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.983
PP5
Variant 3-129528778-T-A is Pathogenic according to our data. Variant chr3-129528778-T-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1067776.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
RHONM_000539.3 linkuse as main transcriptc.45T>A p.Asn15Lys missense_variant 1/5 ENST00000296271.4

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
RHOENST00000296271.4 linkuse as main transcriptc.45T>A p.Asn15Lys missense_variant 1/51 NM_000539.3 P1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
33
GnomAD4 genome
Cov.:
33

ClinVar

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

Submissions by phenotype

not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 03, 2020This sequence change replaces asparagine with lysine at codon 15 of the RHO protein (p.Asn15Lys). The asparagine residue is highly conserved and there is a moderate physicochemical difference between asparagine and lysine. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Asn15 amino acid residue in RHO. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9483582, 8353500, 31100078). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This missense change has been observed in individual(s) with clinical features of autosomal dominant retinitis pigmentosa (PMID: 30538586, Invitae). This variant is not present in population databases (ExAC no frequency). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.87
BayesDel_addAF
Pathogenic
0.23
D
BayesDel_noAF
Uncertain
0.10
CADD
Benign
21
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.87
D
Eigen
Benign
0.15
Eigen_PC
Benign
0.034
FATHMM_MKL
Uncertain
0.80
D
LIST_S2
Pathogenic
0.99
D
M_CAP
Pathogenic
0.50
D
MetaRNN
Pathogenic
0.98
D
MetaSVM
Pathogenic
1.0
D
MutationAssessor
Pathogenic
3.4
M
MutationTaster
Benign
1.0
D
PrimateAI
Uncertain
0.65
T
PROVEAN
Benign
-2.3
N
REVEL
Pathogenic
0.71
Sift
Pathogenic
0.0
D
Sift4G
Pathogenic
0.0010
D
Polyphen
1.0
D
Vest4
0.91
MutPred
0.85
Gain of ubiquitination at N15 (P = 0.017);
MVP
0.95
MPC
0.93
ClinPred
0.99
D
GERP RS
1.1
Varity_R
0.92
gMVP
0.97

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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: chr3-129247621; API