NM_001478.5:c.263dupG

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_001478.5(B4GALNT1):​c.263dupG​(p.Leu89ProfsTer13) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000125 in 1,610,692 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00013 ( 0 hom. )

Consequence

B4GALNT1
NM_001478.5 frameshift

Scores

Not classified

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:11

Conservation

PhyloP100: 0.403
Variant links:
Genes affected
B4GALNT1 (HGNC:4117): (beta-1,4-N-acetyl-galactosaminyltransferase 1) GM2 and GD2 gangliosides are sialic acid-containing glycosphingolipids. GalNAc-T is the enzyme involved in the biosynthesis of G(M2) and G(D2) glycosphingolipids. GalNAc-T catalyzes the transfer of GalNAc into G(M3) and G(D3) by a beta-1,4 linkage, resulting in the synthesis of G(M2) and G(D2), respectively. Three transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Feb 2013]

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 12-57631319-G-GC is Pathogenic according to our data. Variant chr12-57631319-G-GC is described in ClinVar as [Likely_pathogenic]. Clinvar id is 60525.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
B4GALNT1NM_001478.5 linkc.263dupG p.Leu89ProfsTer13 frameshift_variant Exon 3 of 11 ENST00000341156.9 NP_001469.1 Q00973-1B4DSP5

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
B4GALNT1ENST00000341156.9 linkc.263dupG p.Leu89ProfsTer13 frameshift_variant Exon 3 of 11 1 NM_001478.5 ENSP00000341562.4 Q00973-1

Frequencies

GnomAD3 genomes
AF:
0.0000528
AC:
8
AN:
151652
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000727
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:
0.0000737
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
0.000132
AC:
193
AN:
1459040
Hom.:
0
Cov.:
32
AF XY:
0.000143
AC XY:
104
AN XY:
725892
show subpopulations
Gnomad4 AFR exome
AF:
0.000150
Gnomad4 AMR exome
AF:
0.0000895
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000504
Gnomad4 SAS exome
AF:
0.0000464
Gnomad4 FIN exome
AF:
0.00156
Gnomad4 NFE exome
AF:
0.0000793
Gnomad4 OTH exome
AF:
0.000116
GnomAD4 genome
AF:
0.0000528
AC:
8
AN:
151652
Hom.:
0
Cov.:
32
AF XY:
0.0000810
AC XY:
6
AN XY:
74054
show subpopulations
Gnomad4 AFR
AF:
0.0000727
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:
0.0000737
Gnomad4 OTH
AF:
0.00
EpiCase
AF:
0.000109
EpiControl
AF:
0.0000594

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:11
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Hereditary spastic paraplegia 26 Pathogenic:7
-
Juno Genomics, Hangzhou Juno Genomics, Inc
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

PVS1+PM3+PM2_Supporting -

Oct 27, 2023
Baylor Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Aug 01, 2019
Section for Clinical Neurogenetics, University of Tübingen
Significance: Likely pathogenic
Review Status: no assertion criteria provided
Collection Method: research

- -

Feb 07, 2024
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The p.Leu89ProfsX13 variant in B4GALNT1 has been reported in the homozygous state, in at least 3 individuals with hereditary spastic paraplegia (Boukhris 2013 PMID: 23746551, Rose 2020 PMID: 31812852, Hengel 2020 PMID: 32214227). At least two of these individuals were from consanguineous parents. This variant has also been reported by other clinical laboratories in ClinVar (Variation ID 60525) and has been identified in 0.01% (5/67846) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org, v3.1.2). This is consistent with the prevalence of the disease in the general population. In vitro functional studies provide some evidence that this variant impacts protein function as in vitro cell-free enzyme assays showed no residual enzyme activity for this variant (Bhuiyan 2019 PMID: 30521973). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 89 and leads to a premature termination codon 13 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Biallelic loss of function of the B4GALNT1 gene is an established disease mechanism in autosomal recessive hereditary spastic paraplegia. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive hereditary spastic paraplegia. ACMG/AMP Criteria applied: PVS1, PM3, PM2_Supporting, PS3_Supporting. -

-
Genomics England Pilot Project, Genomics England
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jul 11, 2013
OMIM
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: literature only

- -

Feb 22, 2019
Knight Diagnostic Laboratories, Oregon Health and Sciences University
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

not provided Pathogenic:2
Mar 15, 2019
GeneDx
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.263dupG variant in the B4GALNT1 gene has been reported previously in the homozygous state in an individual with hereditary spastic paraplegia with learning disability, lower limb spasticity and weakness, nystagmus, axonal sensitive neuropathy, white matter hyperintensities, and cerebral atrophy (Boukhris et al., 2013). The c.263dupG variant causes a frameshift starting with codon Leucine 89, changes this amino acid to a Proline residue, and creates a premature Stop codon at position 13 of the new reading frame, denoted p.Leu89ProfsX13. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The c.263dupG variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). We interpret c.263dupG as a likely pathogenic variant. -

May 31, 2022
Mayo Clinic Laboratories, Mayo Clinic
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

PM2, PM3, PS3, PVS1 -

Spastic paraplegia Pathogenic:1
Mar 17, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Leu89Profs*13) in the B4GALNT1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in B4GALNT1 are known to be pathogenic (PMID: 23746551). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with hereditary spastic paraplegia (PMID: 23746551, 32214227). ClinVar contains an entry for this variant (Variation ID: 60525). For these reasons, this variant has been classified as Pathogenic. -

Inborn genetic diseases Pathogenic:1
Mar 14, 2017
Ambry Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.040
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: rs745744124; hg19: chr12-58025102; API