12-57631319-GC-GCC

Position:

• chr12-57631319-GC-GCC

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_001478.5(B4GALNT1):​c.263_264insG​(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
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10
• Conservation: PhyloP100: 0.403

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]

ACMG classification

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/exons	MANE	Protein	UniProt
B4GALNT1	NM_001478.5	c.263_264insG	p.Leu89ProfsTer13	frameshift_variant	3/11	ENST00000341156.9	NP_001469.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
B4GALNT1	ENST00000341156.9	c.263_264insG	p.Leu89ProfsTer13	frameshift_variant	3/11	1	NM_001478.5	ENSP00000341562	P1

Frequencies

GnomAD3 genomes AF: 0.0000528 AC: 8 AN: 151652 Hom.: 0 Cov.: 32

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

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

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:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary spastic paraplegia 26 Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Genomics England Pilot Project, Genomics England	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Knight Diagnostic Laboratories, Oregon Health and Sciences University	Feb 22, 2019	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 11, 2013	- -
Likely pathogenic, no assertion criteria provided	research	Section for Clinical Neurogenetics, University of Tübingen	Aug 01, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 07, 2024	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 27, 2023	- -

not provided Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 15, 2019	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	May 31, 2022	PM2, PM3, PS3, PVS1 -

Spastic paraplegia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Mar 07, 2023

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 60525). This premature translational stop signal has been observed in individual(s) with hereditary spastic paraplegia (PMID: 23746551, 32214227). 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 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). -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 14, 2017

- -

Computational scores

Source: dbNSFP v4.3

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

Other links and lift over

dbSNP: rs745744124; hg19: chr12-58025102;