X-74739500-T-C
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1
The NM_001008537.3(NEXMIF):c.4458-2A>G variant causes a splice acceptor change. The variant allele was found at a frequency of 0.00000515 in 1,164,695 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Consequence
NM_001008537.3 splice_acceptor
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
NEXMIF | NM_001008537.3 | c.4458-2A>G | splice_acceptor_variant | ENST00000055682.12 | NP_001008537.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
NEXMIF | ENST00000055682.12 | c.4458-2A>G | splice_acceptor_variant | 1 | NM_001008537.3 | ENSP00000055682 | P1 | |||
NEXMIF | ENST00000616200.2 | c.4458-2A>G | splice_acceptor_variant | 1 | ENSP00000480284 | P1 | ||||
NEXMIF | ENST00000642681.2 | c.*596A>G | 3_prime_UTR_variant | 3/3 | ENSP00000495800 |
Frequencies
GnomAD3 genomes AF: 0.0000184 AC: 2AN: 108804Hom.: 0 Cov.: 21 AF XY: 0.00 AC XY: 0AN XY: 31114
GnomAD4 exome AF: 0.00000379 AC: 4AN: 1055891Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0AN XY: 325419
GnomAD4 genome AF: 0.0000184 AC: 2AN: 108804Hom.: 0 Cov.: 21 AF XY: 0.00 AC XY: 0AN XY: 31114
ClinVar
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jan 29, 2021 | Canonical splice site variant predicted to result in an in-frame deletion of exon 4 which is the last exon; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 27358180) - |
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jun 18, 2023 | This variant has not been reported in the literature in individuals affected with NEXMIF-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change affects an acceptor splice site in intron 3 of the NEXMIF gene. While this variant is not anticipated to result in nonsense mediated decay, it likely alters RNA splicing and results in a disrupted protein product. ClinVar contains an entry for this variant (Variation ID: 1302372). 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. 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at