X-101837488-C-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong

The ENST00000263032.5(ENSG00000290798):​n.1442+4G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000826 in 1,210,359 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. 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 0.000045 ( 0 hom., 1 hem., cov: 23)
Exomes 𝑓: 0.0000046 ( 0 hom. 1 hem. )

Consequence

ENSG00000290798
ENST00000263032.5 splice_region, intron

Scores

2
Splicing: ADA: 0.007733
2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.971
Variant links:
Genes affected
NXF5 (HGNC:8075): (nuclear RNA export factor 5) This gene is one member of a family of nuclear RNA export factor genes. Most transcript variants are candidates for nonsense-mediated decay (NMD) and may not express proteins in vivo. [provided by RefSeq, Sep 2022]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.73).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
NXF5NR_159736.1 linkn.1257G>A non_coding_transcript_exon_variant Exon 13 of 17
NXF5NR_028089.1 linkn.1442+4G>A splice_region_variant, intron_variant Intron 15 of 18
NXF5NR_159737.1 linkn.1253+4G>A splice_region_variant, intron_variant Intron 13 of 16

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ENSG00000290798ENST00000332614.6 linkn.1257G>A non_coding_transcript_exon_variant Exon 13 of 17 1
ENSG00000290798ENST00000263032.5 linkn.1442+4G>A splice_region_variant, intron_variant Intron 15 of 18 1
ENSG00000290798ENST00000361330.5 linkn.1253+4G>A splice_region_variant, intron_variant Intron 13 of 16 1

Frequencies

GnomAD3 genomes
AF:
0.0000446
AC:
5
AN:
112058
Hom.:
0
Cov.:
23
AF XY:
0.0000292
AC XY:
1
AN XY:
34212
show subpopulations
Gnomad AFR
AF:
0.000162
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:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
0.00000455
AC:
5
AN:
1098249
Hom.:
0
Cov.:
33
AF XY:
0.00000275
AC XY:
1
AN XY:
363605
show subpopulations
Gnomad4 AFR exome
AF:
0.000152
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:
0.00
Gnomad4 OTH exome
AF:
0.0000217
GnomAD4 genome
AF:
0.0000446
AC:
5
AN:
112110
Hom.:
0
Cov.:
23
AF XY:
0.0000292
AC XY:
1
AN XY:
34274
show subpopulations
Gnomad4 AFR
AF:
0.000162
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000491

ClinVar

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

Submissions by phenotype

not provided Uncertain:1
Apr 23, 2023
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change falls in intron 15 of the NXF5 gene. It does not directly change the encoded amino acid sequence of the NXF5 protein. It affects a nucleotide within the consensus splice site. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with NXF5-related conditions. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.73
CADD
Benign
3.4
DANN
Benign
0.91

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
0.0077
dbscSNV1_RF
Benign
0.48
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: rs746365654; hg19: chrX-101092460; API