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GeneBe

11-62794271-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2PP2BP4

The NM_006362.5(NXF1):ā€‹c.1747G>Cā€‹(p.Glu583Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000062 in 1,613,642 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: š‘“ 0.000026 ( 0 hom., cov: 32)
Exomes š‘“: 0.0000041 ( 0 hom. )

Consequence

NXF1
NM_006362.5 missense

Scores

1
5
13

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.54
Variant links:
Genes affected
NXF1 (HGNC:8071): (nuclear RNA export factor 1) This gene is one member of a family of nuclear RNA export factor genes. Common domain features of this family are a noncanonical RNP-type RNA-binding domain (RBD), 4 leucine-rich repeats (LRRs), a nuclear transport factor 2 (NTF2)-like domain that allows heterodimerization with NTF2-related export protein-1 (NXT1), and a ubiquitin-associated domain that mediates interactions with nucleoporins. The LRRs and NTF2-like domains are required for export activity. Alternative splicing seems to be a common mechanism in this gene family. The encoded protein of this gene shuttles between the nucleus and the cytoplasm and binds in vivo to poly(A)+ RNA. It is the vertebrate homologue of the yeast protein Mex67p. The encoded protein overcomes the mRNA export block caused by the presence of saturating amounts of CTE (constitutive transport element) RNA of type D retroviruses. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2008]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant where missense usually causes diseases, NXF1
BP4
Computational evidence support a benign effect (MetaRNN=0.3796997).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
NXF1NM_006362.5 linkuse as main transcriptc.1747G>C p.Glu583Gln missense_variant 19/21 ENST00000294172.7

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
NXF1ENST00000294172.7 linkuse as main transcriptc.1747G>C p.Glu583Gln missense_variant 19/211 NM_006362.5 P1Q9UBU9-1

Frequencies

GnomAD3 genomes
AF:
0.0000263
AC:
4
AN:
152154
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000131
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:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000239
AC:
6
AN:
251150
Hom.:
0
AF XY:
0.00000737
AC XY:
1
AN XY:
135726
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000145
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:
0.00000881
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000411
AC:
6
AN:
1461370
Hom.:
0
Cov.:
31
AF XY:
0.00000413
AC XY:
3
AN XY:
726902
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000671
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:
0.00000270
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000263
AC:
4
AN:
152272
Hom.:
0
Cov.:
32
AF XY:
0.0000134
AC XY:
1
AN XY:
74450
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.000131
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000113
ExAC
AF:
0.0000330
AC:
4

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsNov 06, 2023The c.1747G>C (p.E583Q) alteration is located in exon 19 (coding exon 19) of the NXF1 gene. This alteration results from a G to C substitution at nucleotide position 1747, causing the glutamic acid (E) at amino acid position 583 to be replaced by a glutamine (Q). 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
0.43
BayesDel_addAF
Benign
-0.22
T
BayesDel_noAF
Benign
-0.30
CADD
Uncertain
24
DANN
Uncertain
1.0
DEOGEN2
Benign
0.13
T;T
Eigen
Uncertain
0.41
Eigen_PC
Uncertain
0.42
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Benign
0.82
T;.
M_CAP
Benign
0.021
T
MetaRNN
Benign
0.38
T;T
MetaSVM
Benign
-0.96
T
MutationAssessor
Benign
1.8
L;L
MutationTaster
Benign
1.0
D;D;D
PrimateAI
Uncertain
0.78
T
PROVEAN
Benign
-1.4
N;N
REVEL
Benign
0.20
Sift
Benign
0.31
T;T
Sift4G
Benign
0.29
T;T
Polyphen
0.98
D;D
Vest4
0.65
MVP
0.64
MPC
1.5
ClinPred
0.55
D
GERP RS
4.3
Varity_R
0.49
gMVP
0.65

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.030
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: rs138193807; hg19: chr11-62561743; API