5-93585448-G-A

Variant names:

• chr5-93585448-G-A
• rs1554074684
• NM_005654.6:c.425G>A

Variant summary

Our verdict is Pathogenic. The variant received 19 ACMG points: 19P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_005654.6(NR2F1):​c.425G>A​(p.Arg142His) 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. R142C) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 31)
• Consequence: NR2F1 NM_005654.6 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 9.71
• 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 19 ACMG points.

• PM1: In a hotspot region, there are 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 2 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 chr5-93585447-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 280552.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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, 0.985
• PP5: Variant 5-93585448-G-A is Pathogenic according to our data. Variant chr5-93585448-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 520777.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005654.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NR2F1	NM_005654.6	MANE Select	c.425G>A	p.Arg142His	missense	Exon 1 of 3	NP_005645.1
	NR2F1-AS1	NR_186215.1		n.142C>T		non_coding_transcript_exon	Exon 1 of 7
	NR2F1-AS1	NR_186216.1		n.142C>T		non_coding_transcript_exon	Exon 1 of 7

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NR2F1	ENST00000327111.8	TSL:1 MANE Select	c.425G>A	p.Arg142His	missense	Exon 1 of 3	ENSP00000325819.3
	NR2F1	ENST00000615873.2	TSL:1	c.350G>A	p.Arg117His	missense	Exon 2 of 4	ENSP00000481517.1
	NR2F1	ENST00000647447.1		c.272G>A	p.Arg91His	missense	Exon 2 of 4	ENSP00000495740.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Pathogenic:1

Sep 18, 2015

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Pathogenic:1

Mar 16, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 26986877, 32484994)

Bosch-Boonstra-Schaaf optic atrophy syndrome Pathogenic:1

Aug 04, 2017

Equipe Genetique des Anomalies du Developpement, Université de Bourgogne

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.59	D
BayesDel_noAF	Pathogenic	0.61
CADD	Pathogenic	35
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.97	D
Eigen	Pathogenic	0.92
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.92	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.4	H
PhyloP100		9.7
PrimateAI	Pathogenic	0.94	D
PROVEAN	Uncertain	-4.2	D
REVEL	Pathogenic	0.98
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.87
MutPred		0.91		Loss of MoRF binding (P = 0.0158)
MVP		0.97
ClinPred		1.0	D
GERP RS		3.7
PromoterAI		-0.0042	Neutral
Varity_R		0.87
gMVP		0.99
Mutation Taster		=0/100	disease causing (ClinVar)

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: rs1554074684; hg19: chr5-92921154; COSMIC: COSV100504673; COSMIC: COSV100504673;