5-93585037-T-C

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2PP2BP4BP6

The NM_005654.6(NR2F1):c.14T>C(p.Val5Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000389 in 1,027,888 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000021 ( 0 hom., cov: 30)

Exomes 𝑓: 0.0000011 ( 0 hom. )

Consequence

NR2F1
NM_005654.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: 1.69

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 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=0.32285988).

BP6

Variant 5-93585037-T-C is Benign according to our data. Variant chr5-93585037-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 2194431.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NR2F1	NM_005654.6 link	c.14T>C	p.Val5Ala	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.14T>C	p.Val5Ala	missense_variant	Exon 1 of 3	1	NM_005654.6	ENSP00000325819.3		P10589

Frequencies

GnomAD3 genomes

AF:

0.0000206

AC:

AN:

145428

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000248

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:

0.0000152

Gnomad OTH

AF:

0.000495

GnomAD4 exome

AF:

0.00000113

AC:

AN:

882460

Hom.:

Cov.:

AF XY:

0.00000241

AC XY:

AN XY:

415312

show subpopulations

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:

0.00000126

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000206

AC:

AN:

145428

Hom.:

Cov.:

AF XY:

0.0000283

AC XY:

AN XY:

70700

show subpopulations

Gnomad4 AFR

AF:

0.0000248

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:

0.0000152

Gnomad4 OTH

AF:

0.000495

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Aug 12, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.14T>C (p.V5A) alteration is located in exon 1 (coding exon 1) of the NR2F1 gene. This alteration results from a T to C substitution at nucleotide position 14, causing the valine (V) at amino acid position 5 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided

Benign:1

Oct 23, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.34

BayesDel_addAF

Uncertain

0.072

BayesDel_noAF

Benign

-0.13

CADD

Benign

DANN

Benign

0.95

DEOGEN2

Benign

0.11

T;T;.;T

Eigen

Benign

-0.40

Eigen_PC

Benign

-0.33

FATHMM_MKL

Benign

0.48

LIST_S2

Benign

0.78

.;T;T;T

M_CAP

Pathogenic

0.77

MetaRNN

Benign

0.32

T;T;T;T

MetaSVM

Uncertain

-0.059

MutationAssessor

Benign

0.0

N;N;.;.

PrimateAI

Pathogenic

0.93

PROVEAN

Benign

0.10

.;N;.;.

REVEL

Uncertain

0.34

Sift

Benign

0.13

.;T;.;.

Sift4G

Benign

0.56

.;T;.;T

Polyphen

0.0

B;B;.;.

Vest4

0.40, 0.25

MutPred

0.23

Loss of sheet (P = 0.0315);Loss of sheet (P = 0.0315);Loss of sheet (P = 0.0315);Loss of sheet (P = 0.0315);

MVP

0.92

ClinPred

0.34

GERP RS

2.3

Varity_R

0.11

gMVP

0.20

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over