5-93584991-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Moderate BP6_Moderate BS1 BS2

The NM_005654.6(NR2F1):c.-33C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00187 in 980,696 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00095 (0 hom., cov: 30)
  • Exomes 𝑓: 0.0020 (2 hom.)
• Consequence: NR2F1 NM_005654.6 5_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 3.24

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 Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.35).
• BP6: Variant 5-93584991-C-T is Benign according to our data. Variant chr5-93584991-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 380104.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000946 (138/145948) while in subpopulation NFE AF= 0.00187 (123/65704). AF 95% confidence interval is 0.0016. There are 0 homozygotes in gnomad4. There are 58 alleles in male gnomad4 subpopulation. Median coverage is 30. This position pass quality control queck.
• BS2: High AC in GnomAd at 138 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NR2F1	NM_005654.6	c.-33C>T		5_prime_UTR_variant	1/3	ENST00000327111.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NR2F1	ENST00000327111.8	c.-33C>T		5_prime_UTR_variant	1/3	1	NM_005654.6	P1

Frequencies

GnomAD3 genomes AF: 0.000946 AC: 138 AN: 145842 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.000246

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000272

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: 0.00187

Gnomad OTH AF: 0.000494

GnomAD3 exomes AF: 0.00105 AC: 5 AN: 4748 Hom.: 0 AF XY: 0.00146 AC XY: 4 AN XY: 2748

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00249

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00120

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00204 AC: 1700 AN: 834748 Hom.: 2 Cov.: 18 AF XY: 0.00193 AC XY: 745 AN XY: 386632

Gnomad4 AFR exome AF: 0.000315

Gnomad4 AMR exome AF: 0.000686

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000574

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00220

Gnomad4 OTH exome AF: 0.000654

GnomAD4 genome AF: 0.000946 AC: 138 AN: 145948 Hom.: 0 Cov.: 30 AF XY: 0.000817 AC XY: 58 AN XY: 71030

Gnomad4 AFR AF: 0.000245

Gnomad4 AMR AF: 0.000271

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00187

Gnomad4 OTH AF: 0.000488

Alfa AF: 0.000636 Hom.: 0

Bravo AF: 0.000979

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Jan 23, 2018

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.35
Cadd	Benign	20
Dann	Uncertain	0.99
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.3

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

LitVar

Other links and lift over

dbSNP: rs372818347; hg19: chr5-92920697;