15-96332114-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP2

The NM_021005.4(NR2F2):​c.9G>A​(p.Met3Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 31)
Exomes 𝑓: 0.0 ( 0 hom. )
Failed GnomAD Quality Control

Consequence

NR2F2
NM_021005.4 missense

Scores

5
8
6

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.22
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
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.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
NR2F2NM_021005.4 linkuse as main transcriptc.9G>A p.Met3Ile missense_variant 1/3 ENST00000394166.8 NP_066285.1 P24468-1F1D8R0
NR2F2NM_001145155.2 linkuse as main transcriptc.44-1962G>A intron_variant NP_001138627.1 P24468-2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
NR2F2ENST00000394166.8 linkuse as main transcriptc.9G>A p.Met3Ile missense_variant 1/31 NM_021005.4 ENSP00000377721.3 P24468-1
NR2F2ENST00000421109.6 linkuse as main transcriptc.44-1962G>A intron_variant 1 ENSP00000401674.2 P24468-2

Frequencies

GnomAD3 genomes
Cov.:
31
GnomAD4 exome
Data not reliable, filtered out with message: AC0
AF:
0.00
AC:
0
AN:
1189236
Hom.:
0
Cov.:
30
AF XY:
0.00
AC XY:
0
AN XY:
578566
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:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
31

ClinVar

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

Submissions by phenotype

not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingGeneDxJan 19, 2024Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.90
BayesDel_addAF
Pathogenic
0.19
D
BayesDel_noAF
Uncertain
0.030
CADD
Uncertain
25
DANN
Uncertain
0.99
DEOGEN2
Benign
0.42
T
Eigen
Benign
-0.0010
Eigen_PC
Benign
0.13
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.90
D
M_CAP
Pathogenic
0.88
D
MetaRNN
Uncertain
0.59
D
MetaSVM
Uncertain
0.15
D
MutationAssessor
Uncertain
2.0
M
PrimateAI
Pathogenic
0.93
D
PROVEAN
Benign
-1.0
N
REVEL
Uncertain
0.47
Sift
Uncertain
0.0080
D
Sift4G
Benign
0.066
T
Polyphen
0.0010
B
Vest4
0.59
MutPred
0.43
Gain of catalytic residue at M3 (P = 0.0524);
MVP
0.95
MPC
1.6
ClinPred
0.93
D
GERP RS
3.6
Varity_R
0.52
gMVP
0.53

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr15-96875343; API