20-57367041-G-T

Variant names:

• chr20-57367041-G-T
• rs761437706
• NM_003610.4:c.496G>T

Variant summary

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

The NM_003610.4(RAE1):​c.496G>T​(p.Val166Phe) variant causes a missense change. The variant allele was found at a frequency of 0.00000658 in 151,996 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V166I) has been classified as Uncertain significance.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: RAE1 NM_003610.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.25

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=0.20709449).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RAE1	NM_003610.4	c.496G>T	p.Val166Phe	missense_variant	Exon 7 of 12	ENST00000395841.7	NP_003601.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RAE1	ENST00000395841.7	c.496G>T	p.Val166Phe	missense_variant	Exon 7 of 12	1	NM_003610.4	ENSP00000379182.2

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 151996 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000946

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251408 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135870

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 32

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 151996 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74236

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000946

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Uncertain	0.027	T
BayesDel_noAF	Benign	-0.20
CADD	Uncertain	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.29	T;T;.;T
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Pathogenic	0.98	.;.;D;D
M_CAP	Benign	0.044	D
MetaRNN	Benign	0.21	T;T;T;T
MetaSVM	Benign	-0.61	T
MutationAssessor	Benign	0.83	L;L;.;L
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-2.1	N;N;N;N
REVEL	Benign	0.23
Sift	Uncertain	0.0010	D;D;D;D
Sift4G	Uncertain	0.0030	D;D;D;D
Polyphen		0.27	B;B;P;B
Vest4		0.38
MutPred		0.43		Loss of sheet (P = 0.302);Loss of sheet (P = 0.302);Loss of sheet (P = 0.302);Loss of sheet (P = 0.302);
MVP		0.41
MPC		1.3
ClinPred		0.60	D
GERP RS		4.9
Varity_R		0.67
gMVP		0.22

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: rs761437706; hg19: chr20-55942097;