chr5-93585072-G-C
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 1P and 0B. PP2
The NM_005654.6(NR2F1):c.49G>C(p.Gly17Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000581 in 1,032,048 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.0000068 ( 0 hom., cov: 30)
Exomes 𝑓: 0.0000056 ( 0 hom. )
Consequence
NR2F1
NM_005654.6 missense
NM_005654.6 missense
Scores
2
6
6
Clinical Significance
Conservation
PhyloP100: 4.51
Genes affected
NR2F1 (HGNC:7975): (nuclear receptor subfamily 2 group F member 1) The protein encoded by this gene is a nuclear hormone receptor and transcriptional regulator. The encoded protein acts as a homodimer and binds to 5'-AGGTCA-3' repeats. Defects in this gene are a cause of Bosch-Boonstra optic atrophy syndrome (BBOAS). [provided by RefSeq, Apr 2014]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 1 ACMG points.
PP2
?
Missense variant where missense usually causes diseases, NR2F1
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NR2F1 | NM_005654.6 | c.49G>C | p.Gly17Arg | missense_variant | 1/3 | ENST00000327111.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NR2F1 | ENST00000327111.8 | c.49G>C | p.Gly17Arg | missense_variant | 1/3 | 1 | NM_005654.6 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000682 AC: 1AN: 146598Hom.: 0 Cov.: 30
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GnomAD4 exome AF: 0.00000565 AC: 5AN: 885450Hom.: 0 Cov.: 30 AF XY: 0.00000479 AC XY: 2AN XY: 417878
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Aug 31, 2023 | This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 17 of the NR2F1 protein (p.Gly17Arg). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with NR2F1-related conditions. ClinVar contains an entry for this variant (Variation ID: 1806205). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Bosch-Boonstra-Schaaf optic atrophy syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | May 06, 2021 | Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3B. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Bosch-Boonstra-Schaaf optic atrophy syndrome (MIM#615722), and a dominant negative mechanism has also been suggested (OMIM, PMID: 24462372, PMID: 26986877). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from glycine to arginine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v3) <0.001 for a dominant condition (1 heterozygote, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v3) (1 heterozygote, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0809 - Previous evidence of pathogenicity for this variant is inconclusive. The variant has previously been reported as a VUS, with no further information available (LOVD). (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - The variant was shown not be maternally inherited from the proband's mother who is considered likely to have the same genetic condition although requires confirmatory clinical investigations. Paternal inheritance information is not currently available. Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Benign
Cadd
Uncertain
Dann
Uncertain
DEOGEN2
Benign
T;T;.;T
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
M_CAP
Pathogenic
D
MetaRNN
Uncertain
D;D;D;D
MetaSVM
Uncertain
D
MutationAssessor
Benign
N;N;.;.
MutationTaster
Benign
D
PrimateAI
Pathogenic
D
Polyphen
P;P;.;.
Vest4
0.29, 0.26
MutPred
Gain of solvent accessibility (P = 0.0086);Gain of solvent accessibility (P = 0.0086);Gain of solvent accessibility (P = 0.0086);Gain of solvent accessibility (P = 0.0086);
MVP
0.66
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
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