chr15-71812110-C-T

Variant names:

• chr15-71812110-C-T
• rs1805022
• NM_014249.4:c.505C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_014249.4(NR2E3):​c.505C>T​(p.Leu169Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00243 in 1,557,238 control chromosomes in the GnomAD database, including 71 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.012 (33 hom., cov: 33)
  • Exomes 𝑓: 0.0013 (38 hom.)
• Consequence: NR2E3 NM_014249.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:6
• Conservation: PhyloP100: 2.83
• Publications: 0 publications found

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]

NR2E3 Gene-Disease associations (from GenCC):

• retinitis pigmentosa 37

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• enhanced S-cone syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Laboratory for Molecular Medicine
• retinitis pigmentosa

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Goldmann-Favre syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.47).
• BP6: Variant 15-71812110-C-T is Benign according to our data. Variant chr15-71812110-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 260367.
• BP7: Synonymous conserved (PhyloP=2.83 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0125 (1900/152302) while in subpopulation AFR AF = 0.0431 (1793/41568). AF 95% confidence interval is 0.0415. There are 33 homozygotes in GnomAd4. There are 828 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 33 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014249.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NR2E3	NM_014249.4	MANE Select	c.505C>T	p.Leu169Leu	synonymous	Exon 4 of 8	NP_055064.1
	NR2E3	NM_016346.4		c.505C>T	p.Leu169Leu	synonymous	Exon 4 of 7	NP_057430.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NR2E3	ENST00000617575.5	TSL:1 MANE Select	c.505C>T	p.Leu169Leu	synonymous	Exon 4 of 8	ENSP00000482504.1
	NR2E3	ENST00000621098.1	TSL:1	c.505C>T	p.Leu169Leu	synonymous	Exon 4 of 7	ENSP00000479962.1
	NR2E3	ENST00000621736.4	TSL:2	c.241C>T	p.Leu81Leu	synonymous	Exon 6 of 10	ENSP00000479254.1

Frequencies

GnomAD3 genomes AF: 0.0124 AC: 1893 AN: 152184 Hom.: 32 Cov.: 33

Gnomad AFR AF: 0.0431

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00484

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.0110

GnomAD2 exomes AF: 0.00297 AC: 487 AN: 163782 AF XY: 0.00226

Gnomad AFR exome AF: 0.0481

Gnomad AMR exome AF: 0.00250

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000761

Gnomad OTH exome AF: 0.00197

GnomAD4 exome AF: 0.00134 AC: 1884 AN: 1404936 Hom.: 38 Cov.: 33 AF XY: 0.00114 AC XY: 791 AN XY: 693652

African (AFR) AF: 0.0480 AC: 1530 AN: 31876

American (AMR) AF: 0.00288 AC: 104 AN: 36166

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25238

East Asian (EAS) AF: 0.00 AC: 0 AN: 36190

South Asian (SAS) AF: 0.0000752 AC: 6 AN: 79782

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48898

Middle Eastern (MID) AF: 0.00123 AC: 7 AN: 5700

European-Non Finnish (NFE) AF: 0.0000443 AC: 48 AN: 1082790

Other (OTH) AF: 0.00324 AC: 189 AN: 58296

GnomAD4 genome AF: 0.0125 AC: 1900 AN: 152302 Hom.: 33 Cov.: 33 AF XY: 0.0111 AC XY: 828 AN XY: 74464

African (AFR) AF: 0.0431 AC: 1793 AN: 41568

American (AMR) AF: 0.00484 AC: 74 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000132 AC: 9 AN: 68020

Other (OTH) AF: 0.0109 AC: 23 AN: 2110

Alfa AF: 0.00316 Hom.: 7

Bravo AF: 0.0141

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	2	Enhanced S-cone syndrome (2)
-	-	1	Goldmann-Favre syndrome (1)
-	-	1	not provided (1)
-	-	1	not specified (1)
-	-	1	Retinitis pigmentosa (1)
-	1	-	Retinitis Pigmentosa, Recessive (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.47
CADD	Benign	5.1
DANN	Benign	0.54
PhyloP100		2.8

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: rs1805022; hg19: chr15-72104450;