5-93585026-G-A

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PVS1 PS1_Moderate PM2 PP5

The NM_005654.6(NR2F1):c.3G>A(p.Met1?) variant causes a start lost 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 Pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: NR2F1 NM_005654.6 start_lost
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 6.08

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.

• PVS1: Start lost variant, no new inframe start found.
• PS1: Another start lost variant in NM_005654.6 (NR2F1) was described as [Pathogenic] in ClinVar as 279855
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 5-93585026-G-A is Pathogenic according to our data. Variant chr5-93585026-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 2683748.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NR2F1	NM_005654.6	c.3G>A	p.Met1?	start_lost	1/3	ENST00000327111.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NR2F1	ENST00000327111.8	c.3G>A	p.Met1?	start_lost	1/3	1	NM_005654.6	P1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 871336 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 408178

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

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

Clinical Genomics Program, Stanford Medicine

Jun 02, 2021

The p.Met1? variant in the NR2F1 gene was identified de novo in this individual, but has not been previously reported in association with disease. This variant was absent from large population databases, including the Genome Aggregation Database (http://gnomad.broadinstitute.org/). The p.Met1? variant disrupts the translation initiation codon and is predicted to result in an abnormal or absent protein. Western blots of different p.Met1? variants in this gene demonstrated reduced protein, suggesting that any p.Met1? variant in this gene could result in loss of function (Chen et al., 2016). Heterozygous loss of function is an established mechanism of disease for the NR2F1 gene. These data were assessed using the ACMG/AMP variant interpretation guidelines. In summary, there is sufficient evidence to classify the p.Met1? variant as pathogenic for autosomal dominant Bosch-Boonstra-Schaaf optic atrophy syndrome based on the information above. [ACMG evidence codes used: PVS1, PS2, PM2] -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.60	D
BayesDel_noAF	Pathogenic	0.34
Cadd	Uncertain	23
Dann	Uncertain	0.99
DEOGEN2	Benign	0.17	T;T;.;T
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.16
FATHMM_MKL	Uncertain	0.90	D
M_CAP	Pathogenic	0.54	D
MetaRNN	Pathogenic	0.79	D;D;D;D
MetaSVM	Uncertain	-0.086	T
MutationTaster	Benign	1.0	N
Polyphen		0.0060	B;B;.;.
Vest4		0.84, 0.86
MutPred		0.67		Gain of catalytic residue at M1 (P = 0.0468);Gain of catalytic residue at M1 (P = 0.0468);Gain of catalytic residue at M1 (P = 0.0468);Gain of catalytic residue at M1 (P = 0.0468);
MVP		0.89
ClinPred		1.0	D
GERP RS		2.3
Varity_R		0.95
gMVP		0.52

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr5-92920732;