5-93585025-T-C

Variant names:

• chr5-93585025-T-C
• rs886041216
• NM_005654.6:c.2T>C

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1_Strong 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:5
• 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 16 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 5 pathogenic variants. Next in-frame start position is after 3 codons. Genomic position: 93585030. Lost 0.006 part of the original CDS.
• 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 rank	MANE	Protein	UniProt
NR2F1	NM_005654.6	c.2T>C	p.Met1?	start_lost	Exon 1 of 3	ENST00000327111.8	NP_005645.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NR2F1	ENST00000327111.8	c.2T>C	p.Met1?	start_lost	Exon 1 of 3	1	NM_005654.6	ENSP00000325819.3

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:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Dec 28, 2021

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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) -

Mar 15, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects the initiator methionine of the NR2F1 mRNA. The next in-frame methionine is located at codon 3. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the gnomAD database. Disruption of the initiator codon has been observed in individuals with Bosch-Boonstra-Schaaf optic atrophy syndrome (PMID: 26986877). ClinVar contains an entry for this variant (Variation ID: 279855). Studies have shown that disruption of the initiator codon alters NR2F1 gene expression (PMID: 26986877). For these reasons, this variant has been classified as Pathogenic. -

Bosch-Boonstra-Schaaf optic atrophy syndrome Pathogenic:2

Aug 28, 2019

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Mar 29, 2021

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Inborn genetic diseases Pathogenic:1

Apr 13, 2021

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

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
LIST_S2	Uncertain	0.90	.;D;D;D
M_CAP	Pathogenic	0.42	D
MetaRNN	Pathogenic	0.81	D;D;D;D
MetaSVM	Uncertain	-0.12	T
PROVEAN	Benign	-1.7	.;N;.;.
REVEL	Uncertain	0.60
Sift	Pathogenic	0.0	.;D;.;.
Sift4G	Pathogenic	0.0	.;D;.;D
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;