5-93585026-G-A

Variant names:

• chr5-93585026-G-A
• rs866011766
• NM_005654.6:c.3G>A

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PVS1_Strong PS1_Moderate PS3 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). ClinVar reports functional evidence for this variant: "SCV004227894: 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).".

• 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
• 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 13 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 5 pathogenic variants. Next in-frame start position is after 3 codons. Genomic position: 93585030. Lost 0.006 part of the original CDS.
• PS1: Another start lost variant in NM_005654.6 (NR2F1) was described as [Pathogenic] in ClinVar
• PS3: PS3 evidence extracted from ClinVar submissions: SCV004227894: 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).
• 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 VariationId is 2683748.Status of the report is no_assertion_criteria_provided, 0 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NR2F1	NM_005654.6	MANE Select	c.3G>A	p.Met1?	start_lost	Exon 1 of 3	NP_005645.1	P10589
	NR2F1-AS1	NR_186215.1		n.206+358C>T		intron	N/A
	NR2F1-AS1	NR_186216.1		n.261+303C>T		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NR2F1	ENST00000327111.8	TSL:1 MANE Select	c.3G>A	p.Met1?	start_lost	Exon 1 of 3	ENSP00000325819.3	P10589
	NR2F1	ENST00000615873.2	TSL:1	c.3G>A	p.Met1?	start_lost	Exon 1 of 4	ENSP00000481517.1	F1DAL9
	NR2F1	ENST00000647447.1		c.3G>A	p.Met1?	start_lost	Exon 1 of 4	ENSP00000495740.1	F1DAL7

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

African (AFR) AF: 0.00 AC: 0 AN: 16732

American (AMR) AF: 0.00 AC: 0 AN: 4086

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 5672

East Asian (EAS) AF: 0.00 AC: 0 AN: 5578

South Asian (SAS) AF: 0.00 AC: 0 AN: 18796

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 2150

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3346

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 786030

Other (OTH) AF: 0.00 AC: 0 AN: 28946

GnomAD4 genome Cov.: 30

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Bosch-Boonstra-Schaaf optic atrophy syndrome (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.16
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.54	D
MetaRNN	Pathogenic	0.79	D
MetaSVM	Uncertain	-0.086	T
PhyloP100		6.1
PROVEAN	Benign	-1.2	N
REVEL	Uncertain	0.55
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.0060	B
Vest4		0.84
MutPred		0.67		Gain of catalytic residue at M1 (P = 0.0468)
MVP		0.89
ClinPred		1.0	D
GERP RS		2.3
PromoterAI		-0.057	Neutral
Varity_R		0.95
gMVP		0.52
Mutation Taster		=7/193	disease causing

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: rs866011766; hg19: chr5-92920732;