15-96332205-C-T

Variant names:

• chr15-96332205-C-T
• rs1899167460
• NM_021005.4:c.100C>T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_021005.4(NR2F2):​c.100C>T​(p.Pro34Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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: not found (cov: 31)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: NR2F2 NM_021005.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.06

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.21027398).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NR2F2	NM_021005.4	c.100C>T	p.Pro34Ser	missense_variant	Exon 1 of 3	ENST00000394166.8	NP_066285.1
NR2F2	NM_001145155.2	c.44-1871C>T		intron_variant	Intron 1 of 2		NP_001138627.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NR2F2	ENST00000394166.8	c.100C>T	p.Pro34Ser	missense_variant	Exon 1 of 3	1	NM_021005.4	ENSP00000377721.3
NR2F2	ENST00000421109.6	c.44-1871C>T		intron_variant	Intron 1 of 2	1		ENSP00000401674.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1200376 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 586404

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

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Apr 27, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.100C>T (p.P34S) alteration is located in exon 1 (coding exon 1) of the NR2F2 gene. This alteration results from a C to T substitution at nucleotide position 100, causing the proline (P) at amino acid position 34 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.058
BayesDel_addAF	Uncertain	0.038	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	22
DANN	Benign	0.96
DEOGEN2	Benign	0.24	T
Eigen	Benign	-0.73
Eigen_PC	Benign	-0.62
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.49	T
M_CAP	Pathogenic	0.83	D
MetaRNN	Benign	0.21	T
MetaSVM	Benign	-0.71	T
MutationAssessor	Benign	0.17	N
PrimateAI	Pathogenic	0.89	D
PROVEAN	Benign	0.34	N
REVEL	Benign	0.28
Sift	Benign	0.35	T
Sift4G	Benign	0.34	T
Polyphen		0.0010	B
Vest4		0.19
MutPred		0.23		Gain of phosphorylation at P34 (P = 0.0104);
MVP		0.63
MPC		1.5
ClinPred		0.12	T
GERP RS		1.4
Varity_R		0.053
gMVP		0.082

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

Other links and lift over

dbSNP: rs1899167460; hg19: chr15-96875434;