4-109842614-A-G
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Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong
The NM_006583.5(RRH):āc.866A>Gā(p.Tyr289Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000031 in 1,613,924 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 Uncertain significance (ā ).
Frequency
Genomes: š 0.000013 ( 0 hom., cov: 32)
Exomes š: 0.0000021 ( 0 hom. )
Consequence
RRH
NM_006583.5 missense
NM_006583.5 missense
Scores
8
7
4
Clinical Significance
Conservation
PhyloP100: 8.84
Genes affected
RRH (HGNC:10450): (retinal pigment epithelium-derived rhodopsin homolog) Opsins are members of the guanine nucleotide-binding protein (G protein)-coupled receptor superfamily. This gene belongs to the seven-exon subfamily of mammalian opsin genes that includes opsin 5 and retinal G protein coupled receptor. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.956
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RRH | NM_006583.5 | c.866A>G | p.Tyr289Cys | missense_variant | 6/7 | ENST00000317735.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RRH | ENST00000317735.7 | c.866A>G | p.Tyr289Cys | missense_variant | 6/7 | 1 | NM_006583.5 | P1 | |
RRH | ENST00000652276.1 | c.446-1469A>G | intron_variant | ||||||
RRH | ENST00000650907.1 | n.1924A>G | non_coding_transcript_exon_variant | 5/6 |
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152174Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00000795 AC: 2AN: 251466Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135908
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GnomAD4 exome AF: 0.00000205 AC: 3AN: 1461750Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1AN XY: 727186
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GnomAD4 genome AF: 0.0000131 AC: 2AN: 152174Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74338
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 16, 2023 | The c.866A>G (p.Y289C) alteration is located in exon 6 (coding exon 6) of the RRH gene. This alteration results from a A to G substitution at nucleotide position 866, causing the tyrosine (Y) at amino acid position 289 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Benign
T
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D
MetaSVM
Benign
T
MutationAssessor
Pathogenic
M
MutationTaster
Benign
D
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D
REVEL
Pathogenic
Sift
Benign
T
Sift4G
Uncertain
D
Polyphen
D
Vest4
MutPred
Gain of ubiquitination at K284 (P = 0.0954);
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at