rs2305795

Positions:

• chr19-10115376-G-A
• chr19-10115376-G-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_003755.5(EIF3G):​c.947+103C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.573 in 1,335,272 control chromosomes in the GnomAD database, including 221,100 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as association (no stars).

• Frequency:
  • Genomes: 𝑓 0.60 (27386 hom., cov: 33)
  • Exomes 𝑓: 0.57 (193714 hom.)
• Consequence: EIF3G NM_003755.5 intron
• Clinical Significance: association no assertion criteria provided O:1
• Conservation: PhyloP100: -1.20

Genes affected

EIF3G (HGNC:3274): (eukaryotic translation initiation factor 3 subunit G) This gene encodes a core subunit of the eukaryotic translation initiation factor 3 (eIF3) complex, which is required for initiation of protein translation. An N-terminal caspase cleavage product of the encoded protein may stimulate degradation of DNA. A mutation in this gene is associated with narcolepsy. [provided by RefSeq, Jul 2016]

EIF3G (HGNC:):

P2RY11 (HGNC:8540): (purinergic receptor P2Y11) The product of this gene belongs to the family of G-protein coupled receptors. This family has several receptor subtypes with different pharmacological selectivity, which overlaps in some cases, for various adenosine and uridine nucleotides. This receptor is coupled to the stimulation of the phosphoinositide and adenylyl cyclase pathways and behaves as a selective purinoceptor. Naturally occuring read-through transcripts, resulting from intergenic splicing between this gene and an immediately upstream gene (PPAN, encoding peter pan homolog), have been found. The PPAN-P2RY11 read-through mRNA is ubiquitously expressed and encodes a fusion protein that shares identity with each individual gene product. [provided by RefSeq, Jul 2008]

PPAN-P2RY11 (HGNC:33526): (PPAN-P2RY11 readthrough) This locus represents naturally occurring read-through transcription between the adjacent PPAN and P2RY11 genes. Alternative splicing results in two transcript variants, one of which encodes a fusion protein that shares sequence identity with each individual gene product. This transcript is found to be ubiquitously expressed and is up-regulated by agents inducing granulocytic differentiation. However, its functional significance in vivo remains unclear. [provided by RefSeq, Nov 2010]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.677 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EIF3G	NM_003755.5	c.947+103C>T		intron_variant		ENST00000253108.9	NP_003746.2
P2RY11	NM_002566.5	c.*638G>A		downstream_gene_variant		ENST00000321826.5	NP_002557.2
PPAN-P2RY11	NM_001040664.3	c.*638G>A		downstream_gene_variant			NP_001035754.1
PPAN-P2RY11	NM_001198690.2	c.*1522G>A		downstream_gene_variant			NP_001185619.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EIF3G	ENST00000253108.9	c.947+103C>T		intron_variant		1	NM_003755.5	ENSP00000253108.3
EIF3G	ENST00000593054.5	c.341+103C>T		intron_variant		5		ENSP00000467187.1
EIF3G	ENST00000590158.1	n.966+103C>T		intron_variant		2
P2RY11	ENST00000321826.5	c.*638G>A		downstream_gene_variant		1	NM_002566.5	ENSP00000323872.4

Frequencies

GnomAD3 genomes AF: 0.596 AC: 90619 AN: 151946 Hom.: 27341 Cov.: 33

Gnomad AFR AF: 0.621

Gnomad AMI AF: 0.520

Gnomad AMR AF: 0.654

Gnomad ASJ AF: 0.558

Gnomad EAS AF: 0.695

Gnomad SAS AF: 0.641

Gnomad FIN AF: 0.604

Gnomad MID AF: 0.503

Gnomad NFE AF: 0.559

Gnomad OTH AF: 0.619

GnomAD4 exome AF: 0.570 AC: 674411 AN: 1183208 Hom.: 193714 Cov.: 17 AF XY: 0.572 AC XY: 335184 AN XY: 585908

Gnomad4 AFR exome AF: 0.613

Gnomad4 AMR exome AF: 0.697

Gnomad4 ASJ exome AF: 0.552

Gnomad4 EAS exome AF: 0.683

Gnomad4 SAS exome AF: 0.632

Gnomad4 FIN exome AF: 0.594

Gnomad4 NFE exome AF: 0.554

Gnomad4 OTH exome AF: 0.580

GnomAD4 genome AF: 0.597 AC: 90730 AN: 152064 Hom.: 27386 Cov.: 33 AF XY: 0.601 AC XY: 44666 AN XY: 74308

Gnomad4 AFR AF: 0.622

Gnomad4 AMR AF: 0.653

Gnomad4 ASJ AF: 0.558

Gnomad4 EAS AF: 0.696

Gnomad4 SAS AF: 0.642

Gnomad4 FIN AF: 0.604

Gnomad4 NFE AF: 0.559

Gnomad4 OTH AF: 0.621

Alfa AF: 0.566 Hom.: 37652

Bravo AF: 0.604

Asia WGS AF: 0.654 AC: 2272 AN: 3478

ClinVar

Significance: association

Submissions summary: Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Cataplexy and narcolepsy Other:1

association, no assertion criteria provided

case-control

Center for Narcolepsy, Stanford University

Dec 10, 2014

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.31
DANN	Benign	0.41

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: rs2305795; hg19: chr19-10226052;