15-96332124-A-G

Position:

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):c.19A>G(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 (★).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00015 ( 1 hom. )

Consequence

NR2F2
NM_021005.4 missense

Scores

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]

NR2F2 links:

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
NR2F2	NM_021005.4 linkuse as main transcript	c.19A>G	p.Thr7Ala	missense_variant	1/3	ENST00000394166.8	NP_066285.1
NR2F2	NM_001145155.2 linkuse as main transcript	c.44-1952A>G		intron_variant			NP_001138627.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NR2F2	ENST00000394166.8 linkuse as main transcript	c.19A>G	p.Thr7Ala	missense_variant	1/3	1	NM_021005.4	ENSP00000377721	P1	P24468-1
NR2F2	ENST00000421109.6 linkuse as main transcript	c.44-1952A>G		intron_variant		1		ENSP00000401674		P24468-2

Frequencies

GnomAD3 genomes

AF:

0.0000330

AC:

AN:

151652

Hom.:

Cov.:

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:

AN:

32720

Hom.:

AF XY:

0.0000525

AC XY:

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.:

Cov.:

AF XY:

0.000152

AC XY:

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:

AN:

151652

Hom.:

Cov.:

AF XY:

0.0000270

AC XY:

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.:

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 submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 02, 2022

In 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

BayesDel_noAF

Benign

-0.33

CADD

Benign

DANN

Benign

0.93

DEOGEN2

Benign

0.29

Eigen

Benign

-0.51

Eigen_PC

Benign

-0.30

FATHMM_MKL

Benign

0.66

LIST_S2

Benign

0.20

M_CAP

Pathogenic

0.92

MetaRNN

Benign

0.16

MetaSVM

Benign

-0.56

MutationAssessor

Benign

0.38

MutationTaster

Benign

1.0

D;N

PrimateAI

Pathogenic

0.88

PROVEAN

Benign

0.38

REVEL

Benign

0.18

Sift

Benign

1.0

Sift4G

Benign

0.92

Polyphen

0.0

Vest4

0.034

MutPred

0.26

Loss of phosphorylation at T7 (P = 0.021);

MVP

0.52

MPC

1.5

ClinPred

0.082

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.

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