chr5-93585025-T-C
Variant summary
Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PVS1PS1_ModeratePM2PP5_Very_Strong
The NM_005654.6(NR2F1):c.2T>C(p.Met1?) variant causes a start lost 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 Pathogenic (★★).
Frequency
Genomes: not found (cov: 30)
Exomes 𝑓: 0.0 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
NR2F1
NM_005654.6 start_lost
NM_005654.6 start_lost
Scores
4
2
5
Clinical Significance
Conservation
PhyloP100: 2.88
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 Pathogenic. Variant got 20 ACMG points.
PVS1
?
Start lost variant, no new inframe start found.
PS1
?
Another start lost variant in NM_005654.6 (NR2F1) was described as [Pathogenic] in ClinVar as 2683748
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 5-93585025-T-C is Pathogenic according to our data. Variant chr5-93585025-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 279855.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NR2F1 | NM_005654.6 | c.2T>C | p.Met1? | start_lost | 1/3 | ENST00000327111.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NR2F1 | ENST00000327111.8 | c.2T>C | p.Met1? | start_lost | 1/3 | 1 | NM_005654.6 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 30
GnomAD3 genomes
?
Cov.:
30
GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 865688Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0AN XY: 404358
GnomAD4 exome
Data not reliable, filtered out with message: AC0
AF:
AC:
0
AN:
865688
Hom.:
Cov.:
29
AF XY:
AC XY:
0
AN XY:
404358
Gnomad4 AFR exome
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Gnomad4 EAS exome
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Gnomad4 FIN exome
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Gnomad4 OTH exome
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GnomAD4 genome ? Cov.: 30
GnomAD4 genome
?
Cov.:
30
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Bosch-Boonstra-Schaaf optic atrophy syndrome Pathogenic:2
Pathogenic, no assertion criteria provided | literature only | OMIM | Mar 29, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Aug 28, 2019 | A heterozygous start-loss variant was identified, NM_005654.5(NR2F1):c.2T>C in exon 1 of 3 of the NR2F1 gene. This start-loss variant is predicted to create a change at amino acid position 1 of the protein, NP_005645.1(NR2F1):p.(Met1?), resulting in the loss of the canonical translation initiation codon. The variant is not present in the gnomAD population database. It has been previously reported in patients with Bosch-Boonstra-Schaaf optic atrophy syndrome (Chen, C.A. et al. (2016)). In addition, functional analysis shows that this variant causes decreased NR2F1 protein level (Chen, C.A. et al. (2016)). Other variants predicted to abolish the canonical translation initiation have been reported as pathogenic (ClinVar; Chen, C.A. et al. (2016)). Based on information available at the time of curation, this variant has been classified as PATHOGENIC. - |
Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 13, 2021 | The c.2T>C (p.M1?) alteration is located in coding exon 1 of the NR2F1 gene and results from a T to C substitution at nucleotide position 1. This alters the methionine residue at the initiation codon (ATG). Sequence variations that modify the initiation codon are expected to result in either loss of translation initiation, N-terminal truncation, or cause a shift in the mRNA reading frame. Based on data from the Genome Aggregation Database (gnomAD), the NR2F1 c.2T>C alteration was not observed, with coverage at this position. This alteration and other alterations affecting the same initiation site have been reported in multiple unrelated patients with Bosch-Boonstra-Schaaf optic atrophy syndrome (Chen. 2016; Rech, 2020). Most of the alterations were reported de novo. Based on the available evidence, this alteration is classified as pathogenic. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Dec 28, 2021 | Functional studies in fibroblasts derived from patients harboring the c.2 T>C variant have demonstrated reduced NR2F1 mRNA and NR2F1 protein levels, suggesting the variant impacts both transcription and translation (Chen et al., 2016), however, additional studies have not been reported; Initiation codon variant in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 26986877, 30945278, 32484994) - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Benign
Dann
Benign
DEOGEN2
Benign
T;T;.;T
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D
MetaSVM
Uncertain
T
MutationTaster
Benign
N
Polyphen
B;B;.;.
Vest4
0.84, 0.89
MutPred
Gain of relative solvent accessibility (P = 0.0023);Gain of relative solvent accessibility (P = 0.0023);Gain of relative solvent accessibility (P = 0.0023);Gain of relative solvent accessibility (P = 0.0023);
MVP
0.92
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at