5-93585358-G-C

Variant names:

• chr5-93585358-G-C
• NM_005654.6:c.335G>C

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Moderate

The NM_005654.6(NR2F1):​c.335G>C​(p.Arg112Thr) 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. 12/20 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. R112K) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 31)
• Consequence: NR2F1 NM_005654.6 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.87

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 13 ACMG points.

• PM1: In a helix (size 10) in uniprot entity COT1_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) 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 chr5-93585358-G-A is described in Lovd as [Pathogenic].
• 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, 0.987
• PP5: Variant 5-93585358-G-C is Pathogenic according to our data. Variant chr5-93585358-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1711605.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NR2F1	NM_005654.6	c.335G>C	p.Arg112Thr	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.335G>C	p.Arg112Thr	missense_variant	Exon 1 of 3	1	NM_005654.6	ENSP00000325819.3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Sep 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

NR2F1: PM2, PM5, PP2, PP3, PP4 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	34
DANN	Uncertain	0.98
DEOGEN2	Pathogenic	0.97	D;D;.;D
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	.;D;D;D
M_CAP	Pathogenic	0.97	D
MetaRNN	Pathogenic	0.99	D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.7	H;H;.;.
PrimateAI	Pathogenic	0.92	D
PROVEAN	Pathogenic	-4.9	.;D;.;.
REVEL	Pathogenic	0.98
Sift	Pathogenic	0.0	.;D;.;.
Sift4G	Pathogenic	0.0	.;D;.;D
Polyphen		1.0	D;D;.;.
Vest4		0.81, 0.82
MutPred		0.92		Loss of MoRF binding (P = 0.0274);Loss of MoRF binding (P = 0.0274);.;.;
MVP		0.98
ClinPred		1.0	D
GERP RS		3.3
Varity_R		0.87
gMVP		0.99

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr5-92921064;