rs1555447237

Variant names:

• chr15-96334573-T-C
• rs1555447237
• NM_021005.4:c.940T>C

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM2 PP3_Strong PP5_Moderate

The NM_021005.4(NR2F2):​c.940T>C​(p.Cys314Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C314Y) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: NR2F2 NM_021005.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.97
• Publications: 0 publications found

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

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.987
• PP5: Variant 15-96334573-T-C is Pathogenic according to our data. Variant chr15-96334573-T-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 522168.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NR2F2	NM_021005.4	c.940T>C	p.Cys314Arg	missense_variant	Exon 2 of 3	ENST00000394166.8	NP_066285.1
NR2F2	NM_001145155.2	c.541T>C	p.Cys181Arg	missense_variant	Exon 2 of 3		NP_001138627.1
NR2F2	NM_001145156.1	c.481T>C	p.Cys161Arg	missense_variant	Exon 2 of 3		NP_001138628.1
NR2F2	NM_001145157.2	c.481T>C	p.Cys161Arg	missense_variant	Exon 2 of 3		NP_001138629.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NR2F2	ENST00000394166.8	c.940T>C	p.Cys314Arg	missense_variant	Exon 2 of 3	1	NM_021005.4	ENSP00000377721.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Pathogenic:1

Oct 31, 2017

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.97	.;D;.;.
Eigen	Pathogenic	0.95
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.97	D;D;D;.
M_CAP	Pathogenic	0.79	D
MetaRNN	Pathogenic	0.99	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.2	.;H;.;.
PhyloP100		8.0
PrimateAI	Pathogenic	0.92	D
PROVEAN	Pathogenic	-9.5	D;D;D;D
REVEL	Pathogenic	0.98
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D
Polyphen		1.0	.;D;.;.
Vest4		0.96
MutPred		0.86		.;Loss of catalytic residue at L315 (P = 0.0134);.;.;
MVP		0.98
MPC		4.1
ClinPred		1.0	D
GERP RS		5.3
Varity_R		0.99
gMVP		0.97
Mutation Taster		=5/95	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs1555447237; hg19: chr15-96877802;