chr15-96332124-A-G

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2BP4_ModerateBS2

The NM_021005.4(NR2F2):ā€‹c.19A>Gā€‹(p.Thr7Ala) variant causes a missense change. The variant allele was found at a frequency of 0.000139 in 1,355,184 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: š‘“ 0.000033 ( 0 hom., cov: 31)
Exomes š‘“: 0.00015 ( 1 hom. )

Consequence

NR2F2
NM_021005.4 missense

Scores

2
17

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.60
Variant links:
Genes affected
NR2F2 (HGNC:7976): (nuclear receptor subfamily 2 group F member 2) This gene encodes a member of the steroid thyroid hormone superfamily of nuclear receptors. The encoded protein is a ligand inducible transcription factor that is involved in the regulation of many different genes. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Mar 2010]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), NR2F2. . Gene score misZ 3.5964 (greater than the threshold 3.09). Trascript score misZ 4.1992 (greater than threshold 3.09). GenCC has associacion of gene with congenital heart defects, multiple types, 4, NR2F2 related multiple congenital anomalies/dysmorphic syndrome.
BP4
Computational evidence support a benign effect (MetaRNN=0.1598244).
BS2
High AC in GnomAd4 at 5 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
NR2F2NM_021005.4 linkuse as main transcriptc.19A>G p.Thr7Ala missense_variant 1/3 ENST00000394166.8 NP_066285.1
NR2F2NM_001145155.2 linkuse as main transcriptc.44-1952A>G intron_variant NP_001138627.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
NR2F2ENST00000394166.8 linkuse as main transcriptc.19A>G p.Thr7Ala missense_variant 1/31 NM_021005.4 ENSP00000377721 P1P24468-1
NR2F2ENST00000421109.6 linkuse as main transcriptc.44-1952A>G intron_variant 1 ENSP00000401674 P24468-2

Frequencies

GnomAD3 genomes
AF:
0.0000330
AC:
5
AN:
151652
Hom.:
0
Cov.:
31
show subpopulations
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:
0.0000737
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000611
AC:
2
AN:
32720
Hom.:
0
AF XY:
0.0000525
AC XY:
1
AN XY:
19030
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000184
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.000152
AC:
183
AN:
1203532
Hom.:
1
Cov.:
30
AF XY:
0.000152
AC XY:
89
AN XY:
586984
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:
0.000181
Gnomad4 OTH exome
AF:
0.000103
GnomAD4 genome
AF:
0.0000330
AC:
5
AN:
151652
Hom.:
0
Cov.:
31
AF XY:
0.0000270
AC XY:
2
AN XY:
74048
show subpopulations
Gnomad4 AFR
AF:
0.00
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:
0.0000737
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000712
Hom.:
0
Bravo
AF:
0.0000604

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Congenital heart defects, multiple types, 4 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpDec 02, 2022In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt NR2F2 protein function. ClinVar contains an entry for this variant (Variation ID: 1016890). This variant has not been reported in the literature in individuals affected with NR2F2-related conditions. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 7 of the NR2F2 protein (p.Thr7Ala). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.059
BayesDel_addAF
Benign
-0.062
T
BayesDel_noAF
Benign
-0.33
CADD
Benign
20
DANN
Benign
0.93
DEOGEN2
Benign
0.29
T
Eigen
Benign
-0.51
Eigen_PC
Benign
-0.30
FATHMM_MKL
Benign
0.66
D
LIST_S2
Benign
0.20
T
M_CAP
Pathogenic
0.92
D
MetaRNN
Benign
0.16
T
MetaSVM
Benign
-0.56
T
MutationAssessor
Benign
0.38
N
MutationTaster
Benign
1.0
D;N
PrimateAI
Pathogenic
0.88
D
PROVEAN
Benign
0.38
N
REVEL
Benign
0.18
Sift
Benign
1.0
T
Sift4G
Benign
0.92
T
Polyphen
0.0
B
Vest4
0.034
MutPred
0.26
Loss of phosphorylation at T7 (P = 0.021);
MVP
0.52
MPC
1.5
ClinPred
0.082
T
GERP RS
3.4
Varity_R
0.038
gMVP
0.18

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.

Other links and lift over

dbSNP: rs901462929; hg19: chr15-96875353; API