5-93585082-C-A

Position:

• chr5-93585082-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_005654.6(NR2F1):​c.59C>A​(p.Pro20His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000489 in 1,021,604 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000069 (0 hom., cov: 30)
  • Exomes 𝑓: 0.0000046 (0 hom.)
• Consequence: NR2F1 NM_005654.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.228

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), NR2F1. . Gene score misZ: 4.1652 (greater than the threshold 3.09). Trascript score misZ: 4.6855 (greater than threshold 3.09). The gene has 51 curated pathogenic missense variants (we use a threshold of 10). The gene has 7 curated benign missense variants. GenCC has associacion of the gene with Bosch-Boonstra-Schaaf optic atrophy syndrome.
• BP4: Computational evidence support a benign effect (MetaRNN=0.29021448).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NR2F1	NM_005654.6	c.59C>A	p.Pro20His	missense_variant	1/3	ENST00000327111.8	NP_005645.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NR2F1	ENST00000327111.8	c.59C>A	p.Pro20His	missense_variant	1/3	1	NM_005654.6	ENSP00000325819.3

Frequencies

GnomAD3 genomes AF: 0.00000688 AC: 1 AN: 145278 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000153

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000456 AC: 4 AN: 876326 Hom.: 0 Cov.: 30 AF XY: 0.00000727 AC XY: 3 AN XY: 412526

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: 0.00000506

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000688 AC: 1 AN: 145278 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 70612

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000153

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 04, 2023

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. 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 tolerated. This variant has not been reported in the literature in individuals affected with NR2F1-related conditions. 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. This sequence change replaces proline, which is neutral and non-polar, with histidine, which is basic and polar, at codon 20 of the NR2F1 protein (p.Pro20His). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Uncertain	0.034	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	19
DANN	Uncertain	0.98
DEOGEN2	Benign	0.086	T;T;.;T
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.23
FATHMM_MKL	Benign	0.55	D
LIST_S2	Benign	0.72	.;T;T;T
M_CAP	Pathogenic	0.97	D
MetaRNN	Benign	0.29	T;T;T;T
MetaSVM	Uncertain	-0.26	T
MutationAssessor	Benign	0.0	N;N;.;.
PrimateAI	Pathogenic	0.92	D
PROVEAN	Benign	0.090	.;N;.;.
REVEL	Uncertain	0.34
Sift	Benign	0.054	.;T;.;.
Sift4G	Uncertain	0.014	.;D;.;D
Polyphen		0.68	P;P;.;.
Vest4		0.27, 0.23
MutPred		0.25		Loss of glycosylation at P23 (P = 0.1426);Loss of glycosylation at P23 (P = 0.1426);Loss of glycosylation at P23 (P = 0.1426);Loss of glycosylation at P23 (P = 0.1426);
MVP		0.45
ClinPred		0.28	T
GERP RS		2.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.098
gMVP		0.26

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: rs1753204907; hg19: chr5-92920788;