Genetic Variant NM_005654.6:c.5C>T (chr5-93585028-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.5C>T(p.Ala2Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000114 in 875,744 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 30)

Exomes 𝑓: 0.0000011 ( 0 hom. )

Consequence

NR2F1
NM_005654.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.60

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.5C>T	p.Ala2Val	missense	Exon 1 of 3	NP_005645.1	P10589
NR2F1-AS1	NR_186215.1		n.206+356G>A		intron	N/A
NR2F1-AS1	NR_186216.1		n.261+301G>A		intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
NR2F1	ENST00000327111.8	TSL:1 MANE Select	c.5C>T	p.Ala2Val	missense	Exon 1 of 3	ENSP00000325819.3	P10589
NR2F1	ENST00000615873.2	TSL:1	c.5C>T	p.Ala2Val	missense	Exon 1 of 4	ENSP00000481517.1	F1DAL9
NR2F1	ENST00000647447.1		c.5C>T	p.Ala2Val	missense	Exon 1 of 4	ENSP00000495740.1	F1DAL7

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000114

AC:

AN:

875744

Hom.:

Cov.:

AF XY:

0.00000243

AC XY:

AN XY:

410906

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

16836

American (AMR)

AF:

0.00

AC:

AN:

4360

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

5766

East Asian (EAS)

AF:

0.00

AC:

AN:

5800

South Asian (SAS)

AF:

0.00

AC:

AN:

18998

European-Finnish (FIN)

AF:

0.00

AC:

AN:

2454

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3348

European-Non Finnish (NFE)

AF:

0.00000127

AC:

AN:

789050

Other (OTH)

AF:

0.00

AC:

AN:

29132

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Bosch-Boonstra-Schaaf optic atrophy syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.94

BayesDel_addAF

Uncertain

0.15

BayesDel_noAF

Uncertain

-0.020

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.22

Eigen

Benign

0.10

Eigen_PC

Benign

0.045

FATHMM_MKL

Uncertain

0.76

LIST_S2

Benign

0.67

M_CAP

Pathogenic

0.80

MetaRNN

Uncertain

0.65

MetaSVM

Uncertain

0.47

MutationAssessor

Benign

0.0

PhyloP100

3.6

PrimateAI

Pathogenic

0.91

PROVEAN

Benign

-1.7

REVEL

Pathogenic

0.67

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.0090

Polyphen

0.81

Vest4

0.38

MutPred

0.41

Loss of MoRF binding (P = 0.1159)

MVP

0.93

ClinPred

0.75

GERP RS

2.3

PromoterAI

-0.045

Neutral

(source)

Varity_R

0.69

gMVP

0.56

Mutation Taster

=45/55

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over