rs1022192010

chr5-93585426-C-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5

The NM_005654.6(NR2F1):c.403C>T(p.Arg135Cys) 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. 13/20 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R135H) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 30)
• Consequence: NR2F1 NM_005654.6 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.69

Genes affected

NR2F1 (HGNC:7975): (nuclear receptor subfamily 2 group F member 1) The protein encoded by this gene is a nuclear hormone receptor and transcriptional regulator. The encoded protein acts as a homodimer and binds to 5'-AGGTCA-3' repeats. Defects in this gene are a cause of Bosch-Boonstra optic atrophy syndrome (BBOAS). [provided by RefSeq, Apr 2014]

NR2F1-AS1 (HGNC:48622): (NR2F1 antisense RNA 1)

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_005654.6
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr5-93585427-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3201928.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP2: Missense variant where missense usually causes diseases, NR2F1
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.976
• PP5: Variant 5-93585426-C-T is Pathogenic according to our data. Variant chr5-93585426-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 559633.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr5-93585426-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NR2F1	NM_005654.6	c.403C>T	p.Arg135Cys	missense_variant	1/3	ENST00000327111.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NR2F1	ENST00000327111.8	c.403C>T	p.Arg135Cys	missense_variant	1/3	1	NM_005654.6	P1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 30

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Bosch-Boonstra-Schaaf optic atrophy syndrome Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals

Jan 22, 2018

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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	34
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.97	D;D;.;D
Eigen	Pathogenic	0.79
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Uncertain	0.94	D
M_CAP	Pathogenic	0.96	D
MetaRNN	Pathogenic	0.98	D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.9	H;H;.;.
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.95	D
Polyphen		1.0	D;D;.;.
Vest4		0.82, 0.83
MutPred		0.86		Loss of MoRF binding (P = 0.0027);Loss of MoRF binding (P = 0.0027);.;.;
MVP		0.98
ClinPred		1.0	D
GERP RS		3.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.88
gMVP		0.98

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: rs1022192010; hg19: chr5-92921132;