Genetic Variant NM_021005.4:c.19A>G (chr15-96332124-A-G) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_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. 14/22 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

Publications

4 publications found

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:

NR2F2-AS1 (HGNC:44222): (NR2F2 antisense RNA 1)

NR2F2-AS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.1598244).

BS2

High AC in GnomAd4 at 5 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_021005.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NR2F2	NM_021005.4	MANE Select	c.19A>G	p.Thr7Ala	missense	Exon 1 of 3	NP_066285.1	F1D8R0
	NR2F2	NM_001145155.2		c.44-1952A>G		intron	N/A	NP_001138627.1	P24468-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
NR2F2	ENST00000394166.8	TSL:1 MANE Select	c.19A>G	p.Thr7Ala	missense	Exon 1 of 3	ENSP00000377721.3	P24468-1
NR2F2	ENST00000421109.6	TSL:1	c.44-1952A>G		intron	N/A	ENSP00000401674.2	P24468-2
NR2F2	ENST00000961130.1		c.19A>G	p.Thr7Ala	missense	Exon 2 of 4	ENSP00000631189.1

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

GnomAD2 exomes

AF:

0.0000611

AC:

AN:

32720

AF XY:

0.0000525

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 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

African (AFR)

AF:

0.00

AC:

AN:

23846

American (AMR)

AF:

0.00

AC:

AN:

12464

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

17154

East Asian (EAS)

AF:

0.00

AC:

AN:

26498

South Asian (SAS)

AF:

0.00

AC:

AN:

47164

European-Finnish (FIN)

AF:

0.00

AC:

AN:

39058

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3468

European-Non Finnish (NFE)

AF:

0.000181

AC:

178

AN:

985488

Other (OTH)

AF:

0.000103

AC:

AN:

48392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

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

AF:

0.0000330

AC:

AN:

151652

Hom.:

Cov.:

AF XY:

0.0000270

AC XY:

AN XY:

74048

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41328

American (AMR)

AF:

0.00

AC:

AN:

15238

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3464

East Asian (EAS)

AF:

0.00

AC:

AN:

5148

South Asian (SAS)

AF:

0.00

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10478

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.0000737

AC:

AN:

67864

Other (OTH)

AF:

0.00

AC:

AN:

2086

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.415

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000604

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Congenital heart defects, multiple types, 4 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.059

BayesDel_addAF

Benign

-0.062

BayesDel_noAF

Benign

-0.33

CADD

Benign

(source)

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

PhyloP100

4.6

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

PromoterAI

0.16

Neutral

(source)

Varity_R

0.038

gMVP

0.18

Mutation Taster

=85/15

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over