rs759315662
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_015909.4(NBAS):c.686_687insT(p.Ser230GlnfsTer4) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000244 in 1,613,722 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.00035 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00023 ( 0 hom. )
Consequence
NBAS
NM_015909.4 frameshift
NM_015909.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 9.10
Genes affected
NBAS (HGNC:15625): (NBAS subunit of NRZ tethering complex) This gene encodes a protein with two leucine zipper domains, a ribosomal protein S14 signature domain and a Sec39 like domain. The protein is thought to be involved in Golgi-to-ER transport. Mutations in this gene are associated with short stature, optic nerve atrophy, and Pelger-Huet anomaly. [provided by RefSeq, Oct 2012]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
?
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 2-15534602-G-GA is Pathogenic according to our data. Variant chr2-15534602-G-GA is described in ClinVar as [Pathogenic]. Clinvar id is 204581.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NBAS | NM_015909.4 | c.686_687insT | p.Ser230GlnfsTer4 | frameshift_variant | 9/52 | ENST00000281513.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NBAS | ENST00000281513.10 | c.686_687insT | p.Ser230GlnfsTer4 | frameshift_variant | 9/52 | 1 | NM_015909.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000355 AC: 54AN: 152166Hom.: 0 Cov.: 32
GnomAD3 genomes
?
AF:
AC:
54
AN:
152166
Hom.:
Cov.:
32
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
AF:
Gnomad FIN
AF:
Gnomad MID
AF:
Gnomad NFE
AF:
Gnomad OTH
AF:
GnomAD3 exomes AF: 0.000350 AC: 88AN: 251404Hom.: 0 AF XY: 0.000339 AC XY: 46AN XY: 135874
GnomAD3 exomes
AF:
AC:
88
AN:
251404
Hom.:
AF XY:
AC XY:
46
AN XY:
135874
Gnomad AFR exome
AF:
Gnomad AMR exome
AF:
Gnomad ASJ exome
AF:
Gnomad EAS exome
AF:
Gnomad SAS exome
AF:
Gnomad FIN exome
AF:
Gnomad NFE exome
AF:
Gnomad OTH exome
AF:
GnomAD4 exome AF: 0.000232 AC: 339AN: 1461556Hom.: 0 Cov.: 32 AF XY: 0.000226 AC XY: 164AN XY: 727112
GnomAD4 exome
AF:
AC:
339
AN:
1461556
Hom.:
Cov.:
32
AF XY:
AC XY:
164
AN XY:
727112
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome ? AF: 0.000355 AC: 54AN: 152166Hom.: 0 Cov.: 32 AF XY: 0.000498 AC XY: 37AN XY: 74342
GnomAD4 genome
?
AF:
AC:
54
AN:
152166
Hom.:
Cov.:
32
AF XY:
AC XY:
37
AN XY:
74342
Gnomad4 AFR
AF:
Gnomad4 AMR
AF:
Gnomad4 ASJ
AF:
Gnomad4 EAS
AF:
Gnomad4 SAS
AF:
Gnomad4 FIN
AF:
Gnomad4 NFE
AF:
Gnomad4 OTH
AF:
Alfa
AF:
Hom.:
Bravo
AF:
EpiCase
AF:
EpiControl
AF:
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:7
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Sep 13, 2017 | The c.686dupT pathogenic variant in the NBAS gene has been reported previously in combination with another NBAS variant in at least two individuals with features of NBAS-related disorder, including early onset recurrent acute liver failure and short stature (Haack et al., 2015; Staufner et al., 2016). The c.686dupT variant causes a frameshift starting with codon Serine 230, changes this amino acid to a Glutamine residue, and creates a premature Stop codon at position 4 of the new reading frame, denoted p.Ser230GlnfsX4. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The c.686dupT variant is observed in 10/6,614 (0.15%) alleles from individuals of Finnish background in the ExAC dataset (Lek et al., 2016). We interpret c.686dupT as a pathogenic variant. - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 25, 2024 | This sequence change creates a premature translational stop signal (p.Ser230Glnfs*4) in the NBAS gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in NBAS are known to be pathogenic (PMID: 26073778, 26541327, 27789416, 28031453). This variant is present in population databases (rs759315662, gnomAD 0.1%). This premature translational stop signal has been observed in individuals with clinical features of SPOH syndrome (PMID: 26073778). ClinVar contains an entry for this variant (Variation ID: 204581). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Mar 01, 2022 | - - |
Infantile liver failure syndrome 2 Pathogenic:2
Pathogenic, no assertion criteria provided | literature only | OMIM | Jul 02, 2015 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Laboratory of Medical Genetics, University of Torino | Nov 07, 2018 | Found in compound heterozygosity with c.6840G>A - |
Acute infantile liver failure due to synthesis defect of mtDNA-encoded proteins Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Nov 05, 2022 | Variant summary: NBAS c.686dupT (p.Ser230GlnfsX4) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic within ClinVar (e.g. c.1213C>T [p.Arg405Ter], c.1987C>T [p.Gln663Ter]). The variant allele was found at a frequency of 0.00041 in 282794 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in NBAS causing Liver Failure Acute Infantile, Type 2 (0.00041 vs 0.0011), allowing no conclusion about variant significance. c.686dupT has been reported in the literature as a biallelic genotype in individuals affected with Recurrant Acute Liver Failture (e.g. Haack_2015, Baldridge_2017, Carli_2019). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six ClinVar submitters have assessed the variant since 2014: all classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
NBAS-related condition Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Dec 11, 2023 | The NBAS c.686dupT variant is predicted to result in a frameshift and premature protein termination (p.Ser230Glnfs*4). This variant has been reported in the compound heterozygous state in two unrelated individuals with acute liver failure (Families 1 and 10, Haack et al. 2015. PubMed ID: 26073778), and a third individual with hepatic, skeletal, ocular, and immunologic features, as well as dysmorphic facies (Patient 2, Carli et al. 2019. PubMed ID: 30825388). This variant is reported in 0.12% of alleles in individuals of European (Finnish) descent in gnomAD. Frameshift variants in NBAS are expected to be pathogenic. This variant is interpreted as pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at