Genetic Variant NM_005654.6:c.1A>C (chr5-93585024-A-C) – ACMG Classification: Pathogenic (10 pts)

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1_StrongPS1_ModeratePM2PP5_Moderate

The NM_005654.6(NR2F1):c.1A>C(p.Met1?) variant causes a initiator codon change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★).

Frequency

Genomes: not found (cov: 30)

Exomes 𝑓: 0.000024 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

NR2F1
NM_005654.6 initiator_codon

Scores

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 3.58

Publications

0 publications found

Variant links:

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 links:

NR2F1-AS1 (HGNC:48622): (NR2F1 antisense RNA 1)

NR2F1-AS1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 10 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

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 5-93585024-A-C is Pathogenic according to our data. Variant chr5-93585024-A-C is described in ClinVar as Pathogenic. ClinVar VariationId is 1700379.Status of the report is criteria_provided_single_submitter, 1 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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
NR2F1	NM_005654.6	MANE Select	c.1A>C	p.Met1?	initiator_codon	Exon 1 of 3	NP_005645.1	P10589
NR2F1-AS1	NR_186215.1		n.206+360T>G		intron	N/A
NR2F1-AS1	NR_186216.1		n.261+305T>G		intron	N/A

Ensembl Transcripts

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

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000243

AC:

AN:

862566

Hom.:

Cov.:

AF XY:

0.0000273

AC XY:

AN XY:

402524

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.000181

AC:

AN:

16568

American (AMR)

AF:

0.000263

AC:

AN:

3800

Ashkenazi Jewish (ASJ)

AF:

0.000182

AC:

AN:

5500

East Asian (EAS)

AF:

0.000197

AC:

AN:

5076

South Asian (SAS)

AF:

0.00

AC:

AN:

18566

European-Finnish (FIN)

AF:

0.00126

AC:

AN:

1586

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3312

European-Non Finnish (NFE)

AF:

0.0000154

AC:

AN:

779636

Other (OTH)

AF:

0.0000351

AC:

AN:

28522

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.275

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Pathogenic

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.42

BayesDel_noAF

Pathogenic

0.36

CADD

Benign

(source)

DANN

Benign

0.87

DEOGEN2

Benign

0.18

Eigen

Benign

-0.32

Eigen_PC

Benign

-0.26

FATHMM_MKL

Benign

0.70

LIST_S2

Uncertain

0.90

M_CAP

Pathogenic

0.52

MetaRNN

Uncertain

0.73

MetaSVM

Uncertain

-0.25

PhyloP100

3.6

PROVEAN

Benign

-0.96

REVEL

Uncertain

0.53

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

0.0060

Vest4

0.84

MutPred

0.68

Loss of MoRF binding (P = 0.0749)

MVP

0.84

ClinPred

1.0

GERP RS

2.3

PromoterAI

-0.064

Neutral

(source)

Varity_R

0.96

gMVP

0.42

Mutation Taster

=9/191

disease causing

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over