rs886041701
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_001008537.3(NEXMIF):c.1441C>T(p.Arg481Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. R481R) has been classified as Likely benign.
Frequency
Genomes: not found (cov: 22)
Exomes 𝑓: 0.0 ( 0 hom. 0 hem. )
Failed GnomAD Quality Control
Consequence
NEXMIF
NM_001008537.3 stop_gained
NM_001008537.3 stop_gained
Scores
2
2
1
Clinical Significance
Conservation
PhyloP100: 2.03
Genes affected
NEXMIF (HGNC:29433): (neurite extension and migration factor) An inversion on the X chromosome which disrupts this gene and a G-protein coupled purinergic receptor gene located in the pseudoautosomal region of the X chromosome has been linked to X linked cognitive disability.[provided by RefSeq, Mar 2009]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
?
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 61 pathogenic variants in the truncated region.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant X-74743116-G-A is Pathogenic according to our data. Variant chrX-74743116-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 280509.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NEXMIF | NM_001008537.3 | c.1441C>T | p.Arg481Ter | stop_gained | 3/4 | ENST00000055682.12 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NEXMIF | ENST00000055682.12 | c.1441C>T | p.Arg481Ter | stop_gained | 3/4 | 1 | NM_001008537.3 | P1 | |
NEXMIF | ENST00000616200.2 | c.1441C>T | p.Arg481Ter | stop_gained | 3/5 | 1 | P1 | ||
NEXMIF | ENST00000642681.2 | c.1441C>T | p.Arg481Ter | stop_gained | 3/3 |
Frequencies
GnomAD3 genomes ? Cov.: 22
GnomAD3 genomes
?
Cov.:
22
GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 1097739Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 363137
GnomAD4 exome
Data not reliable, filtered out with message: AC0
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AN:
1097739
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Cov.:
32
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0
AN XY:
363137
Gnomad4 AFR exome
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GnomAD4 genome ? Cov.: 22
GnomAD4 genome
?
Cov.:
22
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:10
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
X-linked intellectual disability, Cantagrel type Pathogenic:6
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen | Dec 07, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Nov 09, 2021 | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Aug 20, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Clinical Genomics Laboratory, Washington University in St. Louis | Jan 18, 2024 | The NEXMIF c.1441C>T (p.Arg481Ter) variant has been reported to occur de novo in at least one individual and has been described in at least three families with intellectual disability, with both affected males and females described (de Lange IM et al., PMID: 27358180; Stamberger H et al., PMID: 33144681; Webster R et al., PMID: 27568816; Brea-Fern√°ndez AJ et al., PMID: 35322241). This variant has been reported in the ClinVar database as a germline pathogenic variant by nine submitters and is absent from the general population (gnomAD v.2.1.1), indicating it is not a common variant. This variant causes a premature termination codon, which is predicted to lead to nonsense mediated decay. Based on available information and the ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), this variant is classified as pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | May 11, 2022 | This variant was identified as de novo (maternity and paternity confirmed)._x000D_ Criteria applied: PVS1, PS2_MOD, PS4_MOD, PM2_SUP - |
Pathogenic, criteria provided, single submitter | clinical testing | Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India | - | - - |
not provided Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jan 30, 2023 | Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 27568816, 27358180, 33144681, 31175295, 35032046) - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jul 01, 2019 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 07, 2023 | This sequence change creates a premature translational stop signal (p.Arg481*) in the NEXMIF gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in NEXMIF are known to be pathogenic (PMID: 23615299). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with clinical features of NEXMIF-related conditions (PMID: 27358180). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 280509). For these reasons, this variant has been classified as Pathogenic. - |
not specified Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 30, 2020 | The c.1441C>T (p.R481*) alteration, located in exon 3 (coding exon 2) of the KIAA2022 gene, consists of a C to T substitution at nucleotide position 1441. This changes the amino acid from an arginine (R) to a stop codon at amino acid position 481. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. In one study, this mutation was detected in a nonverbal, nonambulatory female who also had intellectual disability, microcephaly, dysmorphic features, and hypotonia (de Lange, 2016). In our internal cohort, this variant occurred de novo in two females; one individual presented with epilepsy while the other presented with hypotonia, developmental delay, and dysmorphic features (Ambry internal data). Based on the available evidence, this alteration is classified as pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
FATHMM_MKL
Uncertain
D
MutationTaster
Benign
A;A
Vest4
GERP RS
Splicing
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Calibrated prediction
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at