Genetic Variant RAE1:c.288+2479C>A (chr20-57359017-C-A) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_003610.4(RAE1):c.288+2479C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000073 in 1,370,474 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.3e-7 ( 0 hom. )

Consequence

RAE1
NM_003610.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.90

Publications

0 publications found

Variant links:

Genes affected

RAE1 (HGNC:9828): (ribonucleic acid export 1) Mutations in the Schizosaccharomyces pombe Rae1 and Saccharomyces cerevisiae Gle2 genes have been shown to result in accumulation of poly(A)-containing mRNA in the nucleus, suggesting that the encoded proteins are involved in RNA export. The protein encoded by this gene is a homolog of yeast Rae1. It contains four WD40 motifs, and has been shown to localize to distinct foci in the nucleoplasm, to the nuclear rim, and to meshwork-like structures throughout the cytoplasm. This gene is thought to be involved in nucleocytoplasmic transport, and in directly or indirectly attaching cytoplasmic mRNPs to the cytoskeleton. Alternatively spliced transcript variants encoding the same protein have been found for this gene. [provided by RefSeq, Jul 2008]

RAE1 links:

MTRNR2L3 (HGNC:37157): (MT-RNR2 like 3 (pseudogene)) Predicted to enable receptor antagonist activity. Predicted to be involved in negative regulation of execution phase of apoptosis. Predicted to be located in cytoplasm and extracellular region. [provided by Alliance of Genome Resources, Apr 2022]

MTRNR2L3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.775

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003610.4. 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
	RAE1	NM_003610.4	MANE Select	c.288+2479C>A		intron	N/A	NP_003601.1	P78406
	RAE1	NM_001015885.2		c.288+2479C>A		intron	N/A	NP_001015885.1	P78406

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
RAE1	ENST00000395841.7	TSL:1 MANE Select	c.288+2479C>A	intron	N/A	ENSP00000379182.2	P78406
RAE1	ENST00000527947.5	TSL:1	c.288+2479C>A	intron	N/A	ENSP00000432609.1	E9PQ57
RAE1	ENST00000395840.6	TSL:1	c.288+2479C>A	intron	N/A	ENSP00000379181.2	P78406

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.30e-7

AC:

AN:

1370474

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

676198

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

30594

American (AMR)

AF:

0.00

AC:

AN:

32468

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24528

East Asian (EAS)

AF:

0.00

AC:

AN:

34896

South Asian (SAS)

AF:

0.00

AC:

AN:

75944

European-Finnish (FIN)

AF:

0.00

AC:

AN:

39880

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3986

European-Non Finnish (NFE)

AF:

9.34e-7

AC:

AN:

1071214

Other (OTH)

AF:

0.00

AC:

AN:

56964

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.095

BayesDel_addAF

Uncertain

0.019

BayesDel_noAF

Benign

-0.21

CADD

Benign

4.6

(source)

DANN

Benign

0.80

DEOGEN2

Benign

0.12

Eigen

Benign

-0.33

Eigen_PC

Benign

-0.51

FATHMM_MKL

Benign

0.54

M_CAP

Benign

0.00099

MetaRNN

Pathogenic

0.77

MetaSVM

Benign

-0.95

PhyloP100

2.9

PROVEAN

Pathogenic

-11

REVEL

Uncertain

0.46

Vest4

0.57

MVP

0.31

ClinPred

0.89

GERP RS

0.42

PromoterAI

0.028

Neutral

(source)

Varity_R

0.77

gMVP

0.0087

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.13

Details are displayed if max score is > 0.2

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over