chr3-15043362-A-G

Variant names:

• chr3-15043362-A-G
• rs648912
• NM_001291694.2:c.*354A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001291694.2(NR2C2):​c.*354A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0479 in 156,624 control chromosomes in the GnomAD database, including 220 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.047 (197 hom., cov: 32)
  • Exomes 𝑓: 0.089 (23 hom.)
• Consequence: NR2C2 NM_001291694.2 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.09
• Publications: 3 publications found

Genes affected

NR2C2 (HGNC:7972): (nuclear receptor subfamily 2 group C member 2) This gene encodes a protein that belongs to the nuclear hormone receptor family. Members of this family act as ligand-activated transcription factors and function in many biological processes such as development, cellular differentiation and homeostasis. The activated receptor/ligand complex is translocated to the nucleus where it binds to hormone response elements of target genes. The protein encoded by this gene plays a role in protecting cells from oxidative stress and damage induced by ionizing radiation. The lack of a similar gene in mouse results in growth retardation, severe spinal curvature, subfertility, premature aging, and prostatic intraepithelial neoplasia (PIN) development. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Apr 2014]

MRPS25 (HGNC:14511): (mitochondrial ribosomal protein S25) Mammalian mitochondrial ribosomal proteins are encoded by nuclear genes and help in protein synthesis within the mitochondrion. Mitochondrial ribosomes (mitoribosomes) consist of a small 28S subunit and a large 39S subunit. They have an estimated 75% protein to rRNA composition compared to prokaryotic ribosomes, where this ratio is reversed. Another difference between mammalian mitoribosomes and prokaryotic ribosomes is that the latter contain a 5S rRNA. Among different species, the proteins comprising the mitoribosome differ greatly in sequence, and sometimes in biochemical properties, which prevents easy recognition by sequence homology. This gene encodes a 28S subunit protein. A pseudogene corresponding to this gene is found on chromosome 4. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2016]

MRPS25 Gene-Disease associations (from GenCC):

• mitochondrial encephalomyopathy

  Inheritance: AR Classification: LIMITED Submitted by: Franklin by Genoox
• combined oxidative phosphorylation deficiency 50

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.65).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0575 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001291694.2. 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
	NR2C2	NM_001291694.2	MANE Select	c.*354A>G		3_prime_UTR	Exon 14 of 14	NP_001278623.1
	NR2C2	NM_003298.5		c.*354A>G		3_prime_UTR	Exon 15 of 15	NP_003289.2
	MRPS25	NR_135246.2		n.3466-340T>C		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NR2C2	ENST00000425241.6	TSL:2 MANE Select	c.*354A>G		3_prime_UTR	Exon 14 of 14	ENSP00000388387.1
	NR2C2	ENST00000617312.4	TSL:1	c.*354A>G		3_prime_UTR	Exon 14 of 14	ENSP00000483059.1
	MRPS25	ENST00000420267.6	TSL:4	n.*6659T>C		non_coding_transcript_exon	Exon 4 of 4	ENSP00000396828.1

Frequencies

GnomAD3 genomes AF: 0.0467 AC: 7099 AN: 151872 Hom.: 197 Cov.: 32

Gnomad AFR AF: 0.0159

Gnomad AMI AF: 0.0746

Gnomad AMR AF: 0.0400

Gnomad ASJ AF: 0.0631

Gnomad EAS AF: 0.0216

Gnomad SAS AF: 0.0475

Gnomad FIN AF: 0.100

Gnomad MID AF: 0.0796

Gnomad NFE AF: 0.0590

Gnomad OTH AF: 0.0548

GnomAD4 exome AF: 0.0893 AC: 414 AN: 4636 Hom.: 23 Cov.: 0 AF XY: 0.0955 AC XY: 236 AN XY: 2470

African (AFR) AF: 0.00476 AC: 1 AN: 210

American (AMR) AF: 0.0934 AC: 17 AN: 182

Ashkenazi Jewish (ASJ) AF: 0.109 AC: 15 AN: 138

East Asian (EAS) AF: 0.0233 AC: 4 AN: 172

South Asian (SAS) AF: 0.135 AC: 13 AN: 96

European-Finnish (FIN) AF: 0.128 AC: 66 AN: 516

Middle Eastern (MID) AF: 0.0714 AC: 1 AN: 14

European-Non Finnish (NFE) AF: 0.0911 AC: 277 AN: 3042

Other (OTH) AF: 0.0752 AC: 20 AN: 266

GnomAD4 genome AF: 0.0467 AC: 7095 AN: 151988 Hom.: 197 Cov.: 32 AF XY: 0.0491 AC XY: 3650 AN XY: 74270

African (AFR) AF: 0.0159 AC: 659 AN: 41528

American (AMR) AF: 0.0400 AC: 610 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.0631 AC: 219 AN: 3468

East Asian (EAS) AF: 0.0218 AC: 113 AN: 5174

South Asian (SAS) AF: 0.0469 AC: 226 AN: 4814

European-Finnish (FIN) AF: 0.100 AC: 1052 AN: 10496

Middle Eastern (MID) AF: 0.0822 AC: 24 AN: 292

European-Non Finnish (NFE) AF: 0.0590 AC: 4010 AN: 67932

Other (OTH) AF: 0.0542 AC: 114 AN: 2104

Alfa AF: 0.0555 Hom.: 84

Bravo AF: 0.0407

Asia WGS AF: 0.0290 AC: 99 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.65
CADD	Benign	8.1
DANN	Benign	0.69
PhyloP100		1.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.1

Splicing

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

Other links and lift over

dbSNP: rs648912; hg19: chr3-15084869;