rs587777275

chr5-93585362-C-Achr5-93585362-C-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1 PM2 PP2 PP3_Strong PP5_Moderate

The NM_005654.6(NR2F1):c.339C>A(p.Ser113Arg) 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 pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 30)
• Consequence: NR2F1 NM_005654.6 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, single submitter P:3
• Conservation: PhyloP100: 0.374

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 11 ACMG points.

• PM1: In a hotspot region, there are 11 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_005654.6
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, NR2F1
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.971
• PP5: Variant 5-93585362-C-A is Pathogenic according to our data. Variant chr5-93585362-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 126494.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr5-93585362-C-A is described in Lovd as [Pathogenic]. Variant chr5-93585362-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NR2F1	NM_005654.6	c.339C>A	p.Ser113Arg	missense_variant	1/3	ENST00000327111.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NR2F1	ENST00000327111.8	c.339C>A	p.Ser113Arg	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/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, single submitter

Submissions by phenotype

Bosch-Boonstra-Schaaf optic atrophy syndrome Pathogenic:3

Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 06, 2014	- -
Pathogenic, criteria provided, single submitter	research	Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine	Sep 09, 2015	This study shows that diverse genetic causes underlie CVI. -
Likely pathogenic, criteria provided, single submitter	research	Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine	Feb 06, 2014	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.45
Cadd	Pathogenic	33
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.93	D;D;.;D
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Uncertain	0.87	D
M_CAP	Pathogenic	0.96	D
MetaRNN	Pathogenic	0.97	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.0	M;M;.;.
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.92	D
Polyphen		1.0	D;D;.;.
Vest4		0.89, 0.96
MutPred		0.85		Loss of catalytic residue at S113 (P = 0.0325);Loss of catalytic residue at S113 (P = 0.0325);.;.;
MVP		0.96
ClinPred		1.0	D
GERP RS		3.3
Varity_R		0.89
gMVP		0.99

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: rs587777275; hg19: chr5-92921068;