Genetic Variant NR2F1:p.Gly18Ala (chr5-93585076-G-C) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 3P and 2B. PM2PP2BP4_Moderate

The NM_005654.6(NR2F1):c.53G>C(p.Gly18Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000113 in 881,366 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G18V) has been classified as Benign.

Frequency

Genomes: not found (cov: 30)

Exomes 𝑓: 0.0000011 ( 0 hom. )

Consequence

NR2F1
NM_005654.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.595

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 1 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=0.18523878).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NR2F1	NM_005654.6 link	c.53G>C	p.Gly18Ala	missense_variant	Exon 1 of 3	ENST00000327111.8	NP_005645.1	P10589

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NR2F1	ENST00000327111.8 link	c.53G>C	p.Gly18Ala	missense_variant	Exon 1 of 3	1	NM_005654.6	ENSP00000325819.3		P10589

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000113

AC:

AN:

881366

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

415510

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

16932

American (AMR)

AF:

0.00

AC:

AN:

4148

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

6026

East Asian (EAS)

AF:

0.00

AC:

AN:

5828

South Asian (SAS)

AF:

0.00

AC:

AN:

19816

European-Finnish (FIN)

AF:

0.00

AC:

AN:

2570

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3338

European-Non Finnish (NFE)

AF:

0.00000126

AC:

AN:

793232

Other (OTH)

AF:

0.00

AC:

AN:

29476

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.091

BayesDel_addAF

Benign

-0.073

BayesDel_noAF

Benign

-0.34

CADD

Benign

(source)

DANN

Benign

0.61

DEOGEN2

Benign

0.096

T;T;.;T

Eigen

Benign

-1.1

Eigen_PC

Benign

-0.99

FATHMM_MKL

Benign

0.69

LIST_S2

Benign

0.72

.;T;T;T

M_CAP

Pathogenic

0.95

MetaRNN

Benign

0.19

T;T;T;T

MetaSVM

Benign

-0.58

MutationAssessor

Benign

0.0

N;N;.;.

PhyloP100

0.59

PrimateAI

Pathogenic

0.92

PROVEAN

Benign

0.19

.;N;.;.

REVEL

Uncertain

0.29

Sift

Benign

0.84

.;T;.;.

Sift4G

Benign

0.81

.;T;.;T

Polyphen

0.0

B;B;.;.

Vest4

0.12, 0.14

MutPred

0.23

Loss of catalytic residue at G18 (P = 0.0346);Loss of catalytic residue at G18 (P = 0.0346);Loss of catalytic residue at G18 (P = 0.0346);Loss of catalytic residue at G18 (P = 0.0346);

MVP

0.12

ClinPred

0.055

GERP RS

1.7

PromoterAI

0.13

Neutral

(source)

Varity_R

0.058

gMVP

0.38

Mutation Taster

=60/40

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over