5-93585367-G-T

Variant names:

• chr5-93585367-G-T
• rs587777274
• NM_005654.6:c.344G>T

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM1 PM2 PM5 PP2 PP3_Strong

The NM_005654.6(NR2F1):​c.344G>T​(p.Arg115Leu) variant causes a missense change. 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R115P) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 30)
• Consequence: NR2F1 NM_005654.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.63
• Publications: 0 publications found

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

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PM1: In a hotspot region, there are 10 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 chr5-93585367-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 126493.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP2: Missense variant in the NR2F1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 51 curated pathogenic missense variants (we use a threshold of 10). The gene has 7 curated benign missense variants. Gene score misZ: 4.1652 (above the threshold of 3.09). Trascript score misZ: 4.6855 (above the threshold of 3.09). GenCC associations: The gene is linked to Bosch-Boonstra-Schaaf optic atrophy syndrome.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.974

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NR2F1	NM_005654.6	c.344G>T	p.Arg115Leu	missense_variant	Exon 1 of 3	ENST00000327111.8	NP_005645.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NR2F1	ENST00000327111.8	c.344G>T	p.Arg115Leu	missense_variant	Exon 1 of 3	1	NM_005654.6	ENSP00000325819.3

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 30

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Bosch-Boonstra-Schaaf optic atrophy syndrome Uncertain:1

Aug 28, 2019

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

A heterozygous missense variant was identified, NM_005654.5(NR2F1):c.344G>T in exon 1 of 3 of the NR2F1 gene. This substitution is predicted to create a major amino acid change from arginine to leucine at position 115 of the protein, NP_005645.1(NR2F1):p.(Arg115Leu). The arginine at this position has moderate conservation (100 vertebrates, UCSC), and is located within the DNA-binding functional domain. In silico software predicts this variant to be pathogenic (PolyPhen, SIFT, CADD, MutationTaster). The variant is not present in the gnomAD population database. It has not been previously reported in clinical cases. A different variant in the same codon resulting in a change to proline has been reported in patients with Bosch-Boonstra-Schaaf optic atrophy syndrome (ClinVar, Bosch, D. et al. (2014)). Based on information available at the time of curation, this variant has been classified as a VARIANT of UNCERTAIN SIGNIFICANCE (VUS) with POTENTIAL CLINICAL RELEVANCE. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.26
CADD	Pathogenic	34
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.84	D;D;.;D
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.96	.;D;D;D
M_CAP	Pathogenic	0.90	D
MetaRNN	Pathogenic	0.97	D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Benign	0.92	L;L;.;.
PhyloP100		6.6
PrimateAI	Pathogenic	0.94	D
PROVEAN	Pathogenic	-5.4	.;D;.;.
REVEL	Pathogenic	0.89
Sift	Pathogenic	0.0	.;D;.;.
Sift4G	Uncertain	0.0020	.;D;.;D
Polyphen		1.0	D;D;.;.
Vest4		0.54, 0.55
MutPred		0.89		Loss of disorder (P = 0.0362);Loss of disorder (P = 0.0362);.;.;
MVP		0.97
ClinPred		1.0	D
GERP RS		3.3
PromoterAI		0.0017	Neutral
Varity_R		0.80
gMVP		0.89
Mutation Taster		=10/90	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs587777274; hg19: chr5-92921073;