15-71811978-C-G

Position:

• chr15-71811978-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The ENST00000617575.5(NR2E3):​c.373C>G​(p.Arg125Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R125Q) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: NR2E3 ENST00000617575.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.56

Genes affected

NR2E3 (HGNC:7974): (nuclear receptor subfamily 2 group E member 3) This protein is part of a large family of nuclear receptor transcription factors involved in signaling pathways. Nuclear receptors have been shown to regulate pathways involved in embryonic development, as well as in maintenance of proper cell function in adults. Members of this family are characterized by discrete domains that function in DNA and ligand binding. This gene encodes a retinal nuclear receptor that is a ligand-dependent transcription factor. Defects in this gene are a cause of enhanced S cone syndrome. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 7 uncertain in ENST00000617575.5
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NR2E3	NM_014249.4	c.373C>G	p.Arg125Gly	missense_variant	4/8	ENST00000617575.5	NP_055064.1
NR2E3	NM_016346.4	c.373C>G	p.Arg125Gly	missense_variant	4/7		NP_057430.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NR2E3	ENST00000617575.5	c.373C>G	p.Arg125Gly	missense_variant	4/8	1	NM_014249.4	ENSP00000482504	P1
NR2E3	ENST00000621098.1	c.373C>G	p.Arg125Gly	missense_variant	4/7	1		ENSP00000479962
NR2E3	ENST00000621736.4	c.109C>G	p.Arg37Gly	missense_variant	6/10	2		ENSP00000479254

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1400240 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 690830

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.66
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.090
CADD	Benign	21
DANN	Benign	0.38
DEOGEN2	Uncertain	0.55	.;D;.
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.34
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.94	D;D;D
MetaRNN	Uncertain	0.55	D;D;D
MetaSVM	Benign	-0.46	T
MutationAssessor	Uncertain	2.5	.;M;M
PrimateAI	Uncertain	0.57	T
Sift4G	Uncertain	0.0050	D;D;D
Polyphen		0.95	.;P;.
Vest4		0.73
MutPred		0.28		.;Loss of solvent accessibility (P = 0.0329);Loss of solvent accessibility (P = 0.0329);
MVP		0.65
ClinPred		0.71	D
GERP RS		3.5
Varity_R		0.17
gMVP		0.65

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: rs786205493; hg19: chr15-72104318;