3-129531005-C-T

Position:

chr3-129531005-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong

The NM_000539.3(RHO):c.491C>T(p.Ala164Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000929 in 1,614,078 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A164E) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000082 ( 0 hom. )

Consequence

RHO
NM_000539.3 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6

Conservation

PhyloP100: 6.08

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]

RHO links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PM1

In a transmembrane_region Helical; Name=4 (size 20) in uniprot entity OPSD_HUMAN there are 30 pathogenic changes around while only 0 benign (100%) 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-A is described in Lovd as [Pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.986

PP5

Variant 3-129531005-C-T is Pathogenic according to our data. 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. Variant chr3-129531005-C-T is described in Lovd as [Pathogenic]. Variant chr3-129531005-C-T is described in Lovd as [Likely_pathogenic]. Variant chr3-129531005-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RHO	NM_000539.3 linkuse as main transcript	c.491C>T	p.Ala164Val	missense_variant	2/5	ENST00000296271.4	NP_000530.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RHO	ENST00000296271.4 linkuse as main transcript	c.491C>T	p.Ala164Val	missense_variant	2/5	1	NM_000539.3	ENSP00000296271	P1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152244

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251336

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135878

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000821

AC:

AN:

1461834

Hom.:

Cov.:

AF XY:

0.0000110

AC XY:

AN XY:

727222

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000899

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152244

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74376

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000189

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Retinitis pigmentosa 4

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Centre for Genomic Medicine, Manchester, Central Manchester University Hospitals

Sep 01, 2020

- -

Cone-rod dystrophy

Pathogenic:1

Pathogenic, no assertion criteria provided

research

Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet

Apr 01, 2018

- -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 12, 2024

This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 164 of the RHO protein (p.Ala164Val). This variant is present in population databases (rs104893793, gnomAD 0.003%). This missense change has been observed in individuals with autosomal dominant retinitis pigmentosa (PMID: 7981701, 11139241, 17488458). ClinVar contains an entry for this variant (Variation ID: 417867). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on RHO protein function. Experimental studies have shown that this missense change affects RHO function (PMID: 9380676, 19913029, 30240733). 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: 8088850, 29847639). 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. -

Retinal dystrophy

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

Dept Of Ophthalmology, Nagoya University

Oct 01, 2023

- -

Congenital stationary night blindness autosomal dominant 1

Pathogenic:1

Pathogenic, no assertion criteria provided

research

Division of Human Genetics, Children's Hospital of Philadelphia

Sep 30, 2015

- -

Retinitis pigmentosa

Pathogenic:1

Pathogenic, no assertion criteria provided

research

Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet

Apr 01, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.97

BayesDel_addAF

Pathogenic

0.25

BayesDel_noAF

Pathogenic

0.20

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.74

Eigen

Pathogenic

0.74

Eigen_PC

Pathogenic

0.68

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.93

M_CAP

Uncertain

0.16

MetaRNN

Pathogenic

0.99

MetaSVM

Uncertain

-0.20

MutationAssessor

Pathogenic

3.3

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.73

PROVEAN

Uncertain

-3.2

REVEL

Uncertain

0.50

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0010

Polyphen

0.99

Vest4

0.91

MutPred

0.94

Loss of catalytic residue at M163 (P = 0.3551);

MVP

0.94

MPC

0.86

ClinPred

1.0

GERP RS

5.3

Varity_R

0.91

gMVP

0.96

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over