20-57367077-G-A

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4BS2

The NM_003610.4(RAE1):​c.532G>A​(p.Val178Met) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000019 in 1,576,274 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000016 ( 0 hom. )

Consequence

RAE1
NM_003610.4 missense, splice_region

Scores

2
13
4
Splicing: ADA: 0.01111
2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.28
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.39017212).
BS2
High AC in GnomAd4 at 7 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
RAE1NM_003610.4 linkc.532G>A p.Val178Met missense_variant, splice_region_variant Exon 7 of 12 ENST00000395841.7 NP_003601.1 P78406

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
RAE1ENST00000395841.7 linkc.532G>A p.Val178Met missense_variant, splice_region_variant Exon 7 of 12 1 NM_003610.4 ENSP00000379182.2 P78406

Frequencies

GnomAD3 genomes
AF:
0.0000460
AC:
7
AN:
152012
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000725
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000655
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000441
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000456
AC:
11
AN:
241292
Hom.:
0
AF XY:
0.0000691
AC XY:
9
AN XY:
130316
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000623
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000812
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000161
AC:
23
AN:
1424262
Hom.:
0
Cov.:
31
AF XY:
0.0000183
AC XY:
13
AN XY:
709928
show subpopulations
Gnomad4 AFR exome
AF:
0.0000628
Gnomad4 AMR exome
AF:
0.0000478
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000120
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000148
Gnomad4 OTH exome
AF:
0.0000339
GnomAD4 genome
AF:
0.0000460
AC:
7
AN:
152012
Hom.:
0
Cov.:
32
AF XY:
0.0000404
AC XY:
3
AN XY:
74250
show subpopulations
Gnomad4 AFR
AF:
0.0000725
Gnomad4 AMR
AF:
0.0000655
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000441
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000142
Hom.:
0
Bravo
AF:
0.0000491
ExAC
AF:
0.0000330
AC:
4
EpiCase
AF:
0.000218
EpiControl
AF:
0.000119

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Feb 28, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.532G>A (p.V178M) alteration is located in exon 7 (coding exon 6) of the RAE1 gene. This alteration results from a G to A substitution at nucleotide position 532, causing the valine (V) at amino acid position 178 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.52
BayesDel_addAF
Benign
-0.085
T
BayesDel_noAF
Benign
-0.17
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.57
D;D;.;D
Eigen
Uncertain
0.57
Eigen_PC
Uncertain
0.51
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.89
.;.;D;D
M_CAP
Uncertain
0.17
D
MetaRNN
Benign
0.39
T;T;T;T
MetaSVM
Uncertain
0.21
D
MutationAssessor
Pathogenic
3.2
M;M;.;M
PrimateAI
Uncertain
0.68
T
PROVEAN
Uncertain
-2.9
D;D;D;D
REVEL
Uncertain
0.44
Sift
Uncertain
0.018
D;D;D;D
Sift4G
Uncertain
0.038
D;D;D;D
Polyphen
1.0
D;D;P;D
Vest4
0.27
MutPred
0.58
Loss of catalytic residue at V178 (P = 0.0442);Loss of catalytic residue at V178 (P = 0.0442);Loss of catalytic residue at V178 (P = 0.0442);Loss of catalytic residue at V178 (P = 0.0442);
MVP
0.72
MPC
2.0
ClinPred
0.66
D
GERP RS
4.0
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.42
gMVP
0.38

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
0.011
dbscSNV1_RF
Benign
0.34
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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs766828256; hg19: chr20-55942133; API