20-57354715-A-G

Variant names:

• chr20-57354715-A-G
• NM_003610.4:c.94A>G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_003610.4(RAE1):​c.94A>G​(p.Ile32Val) variant causes a missense change. The variant allele was found at a frequency of 0.000000704 in 1,420,706 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: RAE1 NM_003610.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.32

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.094193876).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RAE1	NM_003610.4	c.94A>G	p.Ile32Val	missense_variant	Exon 3 of 12	ENST00000395841.7	NP_003601.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RAE1	ENST00000395841.7	c.94A>G	p.Ile32Val	missense_variant	Exon 3 of 12	1	NM_003610.4	ENSP00000379182.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.04e-7 AC: 1 AN: 1420706 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 706530

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.11e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 03, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.94A>G (p.I32V) alteration is located in exon 3 (coding exon 2) of the RAE1 gene. This alteration results from a A to G substitution at nucleotide position 94, causing the isoleucine (I) at amino acid position 32 to be replaced by a valine (V). 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	Benign	0.064
BayesDel_addAF	Benign	-0.099	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	18
DANN	Benign	0.77
DEOGEN2	Benign	0.14	T;T;.;T;T;T;T
Eigen	Benign	-0.16
Eigen_PC	Benign	0.070
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.89	.;.;D;.;D;D;D
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.094	T;T;T;T;T;T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	0.19	N;N;.;.;.;N;.
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-0.58	N;N;N;N;N;N;N
REVEL	Benign	0.056
Sift	Benign	0.75	T;T;T;T;T;T;T
Sift4G	Benign	0.43	T;T;T;T;T;T;T
Polyphen		0.0	B;B;B;.;.;B;.
Vest4		0.25
MutPred		0.23		Loss of methylation at K30 (P = 0.1091);Loss of methylation at K30 (P = 0.1091);Loss of methylation at K30 (P = 0.1091);Loss of methylation at K30 (P = 0.1091);Loss of methylation at K30 (P = 0.1091);Loss of methylation at K30 (P = 0.1091);Loss of methylation at K30 (P = 0.1091);
MVP		0.42
MPC		0.76
ClinPred		0.59	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.19
gMVP		0.068

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr20-55929771;