NM_005654.6:c.257G>T

Variant names:

• chr5-93585280-G-T
• rs1554074665
• NM_005654.6:c.257G>T

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5

The NM_005654.6(NR2F1):​c.257G>T​(p.Cys86Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C86R) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 30)
• Consequence: NR2F1 NM_005654.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 9.53
• Publications: 3 publications found

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

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 2 uncertain in NM_005654.6
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr5-93585279-T-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 928681.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP2: Missense variant in the NR2F1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 51 curated pathogenic missense variants (we use a threshold of 10). The gene has 7 curated benign missense variants. Gene score misZ: 4.1652 (above the threshold of 3.09). Trascript score misZ: 4.6855 (above the threshold of 3.09). GenCC associations: The gene is linked to Bosch-Boonstra-Schaaf optic atrophy syndrome.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.984
• PP5: Variant 5-93585280-G-T is Pathogenic according to our data. Variant chr5-93585280-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 438608.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NR2F1	NM_005654.6	c.257G>T	p.Cys86Phe	missense_variant	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.257G>T	p.Cys86Phe	missense_variant	Exon 1 of 3	1	NM_005654.6	ENSP00000325819.3

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 30

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Bosch-Boonstra-Schaaf optic atrophy syndrome Pathogenic:1 Uncertain:1

Aug 24, 2016

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 01, 2025

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.52
CADD	Pathogenic	34
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.97	D;D;.;D
Eigen	Pathogenic	0.73
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	1.0	.;D;D;D
M_CAP	Pathogenic	0.95	D
MetaRNN	Pathogenic	0.98	D;D;D;D
MetaSVM	Pathogenic	0.97	D
MutationAssessor	Pathogenic	4.3	H;H;.;.
PhyloP100		9.5
PrimateAI	Pathogenic	0.97	D
PROVEAN	Pathogenic	-8.5	.;D;.;.
REVEL	Pathogenic	0.90
Sift	Pathogenic	0.0	.;D;.;.
Sift4G	Pathogenic	0.0	.;D;.;D
Polyphen		1.0	D;D;.;.
Vest4		0.90, 0.93
MutPred		0.86		Gain of catalytic residue at C86 (P = 0.0221);Gain of catalytic residue at C86 (P = 0.0221);.;.;
MVP		0.98
ClinPred		0.99	D
GERP RS		2.3
PromoterAI		0.066	Neutral
Varity_R		0.97
gMVP		1.0
Mutation Taster		=9/91	disease causing

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

Other links and lift over

dbSNP: rs1554074665; hg19: chr5-92920986;