Genetic Variant NR2F1:p.Pro11Leu (chr5-93585055-C-T) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP2

The NM_005654.6(NR2F1):c.32C>T(p.Pro11Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 30)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

NR2F1
NM_005654.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.40

Publications

0 publications found

Variant links:

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 links:

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

NR2F1-AS1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 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.

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
NR2F1	NM_005654.6	MANE Select	c.32C>T	p.Pro11Leu	missense	Exon 1 of 3	NP_005645.1	P10589
NR2F1-AS1	NR_186215.1		n.206+329G>A		intron	N/A
NR2F1-AS1	NR_186216.1		n.261+274G>A		intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
NR2F1	ENST00000327111.8	TSL:1 MANE Select	c.32C>T	p.Pro11Leu	missense	Exon 1 of 3	ENSP00000325819.3	P10589
NR2F1	ENST00000615873.2	TSL:1	c.32C>T	p.Pro11Leu	missense	Exon 1 of 4	ENSP00000481517.1	F1DAL9
NR2F1	ENST00000647447.1		c.32C>T	p.Pro11Leu	missense	Exon 1 of 4	ENSP00000495740.1	F1DAL7

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

890752

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

420746

African (AFR)

AF:

0.00

AC:

AN:

17222

American (AMR)

AF:

0.00

AC:

AN:

5528

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

6286

East Asian (EAS)

AF:

0.00

AC:

AN:

6364

South Asian (SAS)

AF:

0.00

AC:

AN:

20672

European-Finnish (FIN)

AF:

0.00

AC:

AN:

3134

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3402

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

798364

Other (OTH)

AF:

0.00

AC:

AN:

29780

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Uncertain

0.044

BayesDel_noAF

Benign

-0.17

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.19

Eigen

Benign

-0.18

Eigen_PC

Benign

-0.17

FATHMM_MKL

Benign

0.75

LIST_S2

Uncertain

0.96

M_CAP

Pathogenic

0.84

MetaRNN

Uncertain

0.44

MetaSVM

Uncertain

0.22

MutationAssessor

Benign

0.0

PhyloP100

3.4

PrimateAI

Pathogenic

0.91

PROVEAN

Benign

-2.0

REVEL

Uncertain

0.43

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.0040

Polyphen

0.47

Vest4

0.23

MutPred

0.42

Loss of catalytic residue at P11 (P = 0.0093)

MVP

0.83

ClinPred

0.87

GERP RS

1.6

PromoterAI

-0.042

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.17

gMVP

0.35

Mutation Taster

=58/42

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over