15-71810534-C-T

Variant names:

• chr15-71810534-C-T
• rs528679282
• ENST00000621736.4:c.-146-949C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The ENST00000621736.4(NR2E3):​c.-146-949C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000862 in 584,906 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00072 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00091 (3 hom.)
• Consequence: NR2E3 ENST00000621736.4 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.0320
• 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: G2P, Labcorp Genetics (formerly Invitae), 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 15-71810534-C-T is Benign according to our data. Variant chr15-71810534-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 888357.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000723 (110/152244) while in subpopulation SAS AF = 0.00747 (36/4820). AF 95% confidence interval is 0.00555. There are 0 homozygotes in GnomAd4. There are 61 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 3 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000621736.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NR2E3	NM_014249.4	MANE Select	c.-210C>T		upstream_gene	N/A	NP_055064.1	Q9Y5X4-1
	NR2E3	NM_016346.4		c.-210C>T		upstream_gene	N/A	NP_057430.1	F1D8Q9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NR2E3	ENST00000621736.4	TSL:2	c.-146-949C>T		intron	N/A	ENSP00000479254.1	Q8IVZ9
	NR2E3	ENST00000617575.5	TSL:1 MANE Select	c.-210C>T		upstream_gene	N/A	ENSP00000482504.1	Q9Y5X4-1
	NR2E3	ENST00000621098.1	TSL:1	c.-210C>T		upstream_gene	N/A	ENSP00000479962.1	Q9Y5X4-2

Frequencies

GnomAD3 genomes AF: 0.000723 AC: 110 AN: 152126 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000966

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00151

Gnomad ASJ AF: 0.000577

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00746

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000588

Gnomad OTH AF: 0.00239

GnomAD4 exome AF: 0.000911 AC: 394 AN: 432662 Hom.: 3 Cov.: 6 AF XY: 0.00114 AC XY: 255 AN XY: 224548

African (AFR) AF: 0.000253 AC: 3 AN: 11870

American (AMR) AF: 0.000856 AC: 14 AN: 16360

Ashkenazi Jewish (ASJ) AF: 0.000339 AC: 4 AN: 11812

East Asian (EAS) AF: 0.0000386 AC: 1 AN: 25882

South Asian (SAS) AF: 0.00490 AC: 193 AN: 39420

European-Finnish (FIN) AF: 0.0000382 AC: 1 AN: 26194

Middle Eastern (MID) AF: 0.00743 AC: 13 AN: 1750

European-Non Finnish (NFE) AF: 0.000515 AC: 142 AN: 275848

Other (OTH) AF: 0.000978 AC: 23 AN: 23526

GnomAD4 genome AF: 0.000723 AC: 110 AN: 152244 Hom.: 0 Cov.: 32 AF XY: 0.000820 AC XY: 61 AN XY: 74420

African (AFR) AF: 0.0000963 AC: 4 AN: 41550

American (AMR) AF: 0.00150 AC: 23 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.000577 AC: 2 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5164

South Asian (SAS) AF: 0.00747 AC: 36 AN: 4820

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000588 AC: 40 AN: 68004

Other (OTH) AF: 0.00237 AC: 5 AN: 2110

Alfa AF: 0.000741 Hom.: 0

Bravo AF: 0.000650

Asia WGS AF: 0.00231 AC: 8 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Enhanced S-cone syndrome (1)
-	-	1	not provided (1)
-	-	1	Retinitis pigmentosa (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	5.3
DANN	Benign	0.64
PhyloP100		-0.032
PromoterAI		0.0044	Neutral

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs528679282; hg19: chr15-72102874;