5-93585024-A-C

Position:

• chr5-93585024-A-C

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_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
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 3.58

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 12 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• 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 id is 1700379.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NR2F1	NM_005654.6	c.1A>C	p.Met1?	initiator_codon_variant	1/3	ENST00000327111.8	NP_005645.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NR2F1	ENST00000327111.8	c.1A>C	p.Met1?	initiator_codon_variant	1/3	1	NM_005654.6	ENSP00000325819.3

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000243 AC: 21 AN: 862566 Hom.: 0 Cov.: 29 AF XY: 0.0000273 AC XY: 11 AN XY: 402524

Gnomad4 AFR exome AF: 0.000181

Gnomad4 AMR exome AF: 0.000263

Gnomad4 ASJ exome AF: 0.000182

Gnomad4 EAS exome AF: 0.000197

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00126

Gnomad4 NFE exome AF: 0.0000154

Gnomad4 OTH exome AF: 0.0000351

GnomAD4 genome Cov.: 30

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Aug 05, 2022

Initiation codon variant in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.36
CADD	Benign	22
DANN	Benign	0.87
DEOGEN2	Benign	0.18	T;T;.;T
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.26
FATHMM_MKL	Benign	0.70	D
LIST_S2	Uncertain	0.90	.;D;D;D
M_CAP	Pathogenic	0.52	D
MetaRNN	Uncertain	0.73	D;D;D;D
MetaSVM	Uncertain	-0.25	T
PROVEAN	Benign	-0.96	.;N;.;.
REVEL	Uncertain	0.53
Sift	Pathogenic	0.0	.;D;.;.
Sift4G	Pathogenic	0.0	.;D;.;T
Polyphen		0.0060	B;B;.;.
Vest4		0.84, 0.86
MutPred		0.68		Loss of MoRF binding (P = 0.0749);Loss of MoRF binding (P = 0.0749);Loss of MoRF binding (P = 0.0749);Loss of MoRF binding (P = 0.0749);
MVP		0.84
ClinPred		1.0	D
GERP RS		2.3
Varity_R		0.96
gMVP		0.42

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: chr5-92920730;