rs1468965930

Variant names:

• chr5-93585037-T-C
• rs1468965930
• NM_005654.6:c.14T>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 3P and 2B. PM2 PP2 BP4 BP6

The NM_005654.6(NR2F1):​c.14T>C​(p.Val5Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000389 in 1,027,888 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000021 (0 hom., cov: 30)
  • Exomes 𝑓: 0.0000011 (0 hom.)
• Consequence: NR2F1 NM_005654.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 1.69
• 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.32285988).
• BP6: Variant 5-93585037-T-C is Benign according to our data. Variant chr5-93585037-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 2194431.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NR2F1	NM_005654.6	MANE Select	c.14T>C	p.Val5Ala	missense	Exon 1 of 3	NP_005645.1	P10589
	NR2F1-AS1	NR_186215.1		n.206+347A>G		intron	N/A
	NR2F1-AS1	NR_186216.1		n.261+292A>G		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NR2F1	ENST00000327111.8	TSL:1 MANE Select	c.14T>C	p.Val5Ala	missense	Exon 1 of 3	ENSP00000325819.3	P10589
	NR2F1	ENST00000615873.2	TSL:1	c.14T>C	p.Val5Ala	missense	Exon 1 of 4	ENSP00000481517.1	F1DAL9
	NR2F1	ENST00000647447.1		c.14T>C	p.Val5Ala	missense	Exon 1 of 4	ENSP00000495740.1	F1DAL7

Frequencies

GnomAD3 genomes AF: 0.0000206 AC: 3 AN: 145428 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.0000248

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000152

Gnomad OTH AF: 0.000495

GnomAD4 exome AF: 0.00000113 AC: 1 AN: 882460 Hom.: 0 Cov.: 30 AF XY: 0.00000241 AC XY: 1 AN XY: 415312

African (AFR) AF: 0.00 AC: 0 AN: 17050

American (AMR) AF: 0.00 AC: 0 AN: 5196

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 5982

East Asian (EAS) AF: 0.00 AC: 0 AN: 6098

South Asian (SAS) AF: 0.00 AC: 0 AN: 19722

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 2662

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3376

European-Non Finnish (NFE) AF: 0.00000126 AC: 1 AN: 792982

Other (OTH) AF: 0.00 AC: 0 AN: 29392

GnomAD4 genome AF: 0.0000206 AC: 3 AN: 145428 Hom.: 0 Cov.: 30 AF XY: 0.0000283 AC XY: 2 AN XY: 70700

African (AFR) AF: 0.0000248 AC: 1 AN: 40314

American (AMR) AF: 0.00 AC: 0 AN: 14676

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3388

East Asian (EAS) AF: 0.00 AC: 0 AN: 4978

South Asian (SAS) AF: 0.00 AC: 0 AN: 4752

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8364

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 302

European-Non Finnish (NFE) AF: 0.0000152 AC: 1 AN: 65732

Other (OTH) AF: 0.000495 AC: 1 AN: 2022

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.34
BayesDel_addAF	Uncertain	0.072	D
BayesDel_noAF	Benign	-0.13
CADD	Benign	21
DANN	Benign	0.95
DEOGEN2	Benign	0.11	T
Eigen	Benign	-0.40
Eigen_PC	Benign	-0.33
FATHMM_MKL	Benign	0.48	N
LIST_S2	Benign	0.78	T
M_CAP	Pathogenic	0.77	D
MetaRNN	Benign	0.32	T
MetaSVM	Uncertain	-0.059	T
MutationAssessor	Benign	0.0	N
PhyloP100		1.7
PrimateAI	Pathogenic	0.93	D
PROVEAN	Benign	0.10	N
REVEL	Uncertain	0.34
Sift	Benign	0.13	T
Sift4G	Benign	0.56	T
Polyphen		0.0	B
Vest4		0.40
MutPred		0.23		Loss of sheet (P = 0.0315)
MVP		0.92
ClinPred		0.34	T
GERP RS		2.3
PromoterAI		0.078	Neutral
Varity_R		0.11
gMVP		0.20
Mutation Taster		=52/48	polymorphism

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

Other links and lift over

dbSNP: rs1468965930; hg19: chr5-92920743;