5-93585025-T-C

Variant summary

Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PVS1 PS1_Moderate PM2 PP5_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
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• 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]

NR2F1-AS1 (HGNC:48622): (NR2F1 antisense RNA 1)

ACMG classification

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

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 865688 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 404358

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 30

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

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: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.60	D
BayesDel_noAF	Pathogenic	0.16
Cadd	Benign	22
Dann	Benign	0.95
DEOGEN2	Benign	0.26	T;T;.;T
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.25
FATHMM_MKL	Uncertain	0.86	D
M_CAP	Pathogenic	0.42	D
MetaRNN	Pathogenic	0.81	D;D;D;D
MetaSVM	Uncertain	-0.12	T
MutationTaster	Benign	1.0	N
Polyphen		0.018	B;B;.;.
Vest4		0.84, 0.89
MutPred		0.68		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		1.0	D
GERP RS		2.3
Varity_R		0.94
gMVP		0.63

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

Other links and lift over

dbSNP: rs886041216; hg19: chr5-92920731;