rs1753204907

Variant names:

• chr5-93585082-C-A
• rs1753204907
• NM_005654.6:c.59C>A

Variant summary

Our verdict is Uncertain significance. The variant received 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P20L) has been classified 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
• Publications: 0 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.29021448).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005654.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NR2F1	NM_005654.6	MANE Select	c.59C>A	p.Pro20His	missense	Exon 1 of 3	NP_005645.1	P10589
	NR2F1-AS1	NR_186215.1		n.206+302G>T		intron	N/A
	NR2F1-AS1	NR_186216.1		n.261+247G>T		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NR2F1	ENST00000327111.8	TSL:1 MANE Select	c.59C>A	p.Pro20His	missense	Exon 1 of 3	ENSP00000325819.3	P10589
	NR2F1	ENST00000615873.2	TSL:1	c.59C>A	p.Pro20His	missense	Exon 1 of 4	ENSP00000481517.1	F1DAL9
	NR2F1	ENST00000647447.1		c.59C>A	p.Pro20His	missense	Exon 1 of 4	ENSP00000495740.1	F1DAL7

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

African (AFR) AF: 0.00 AC: 0 AN: 16796

American (AMR) AF: 0.00 AC: 0 AN: 3434

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 5908

East Asian (EAS) AF: 0.00 AC: 0 AN: 5520

South Asian (SAS) AF: 0.00 AC: 0 AN: 19408

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 2306

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3330

European-Non Finnish (NFE) AF: 0.00000506 AC: 4 AN: 790368

Other (OTH) AF: 0.00 AC: 0 AN: 29256

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

African (AFR) AF: 0.00 AC: 0 AN: 40440

American (AMR) AF: 0.00 AC: 0 AN: 14672

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3370

East Asian (EAS) AF: 0.00 AC: 0 AN: 4996

South Asian (SAS) AF: 0.00 AC: 0 AN: 4758

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8330

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 296

European-Non Finnish (NFE) AF: 0.0000153 AC: 1 AN: 65528

Other (OTH) AF: 0.00 AC: 0 AN: 1996

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.23
FATHMM_MKL	Benign	0.55	D
LIST_S2	Benign	0.72	T
M_CAP	Pathogenic	0.97	D
MetaRNN	Benign	0.29	T
MetaSVM	Uncertain	-0.26	T
MutationAssessor	Benign	0.0	N
PhyloP100		0.23
PrimateAI	Pathogenic	0.92	D
PROVEAN	Benign	0.090	N
REVEL	Uncertain	0.34
Sift	Benign	0.054	T
Sift4G	Uncertain	0.014	D
Polyphen		0.68	P
Vest4		0.27
MutPred		0.25		Loss of glycosylation at P23 (P = 0.1426)
MVP		0.45
ClinPred		0.28	T
GERP RS		2.6
PromoterAI		-0.0034	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.098
gMVP		0.26
Mutation Taster		=51/49	polymorphism

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: rs1753204907; hg19: chr5-92920788;