chr12-57631074-TG-T

Variant names:

• chr12-57631074-TG-T
• rs766591558
• NM_001478.5:c.395delC

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_001478.5(B4GALNT1):​c.395delC​(p.Pro132GlnfsTer7) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000343 in 1,459,636 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: B4GALNT1 NM_001478.5 frameshift
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.05
• Publications: 0 publications found

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]

B4GALNT1 Gene-Disease associations (from GenCC):

• complex hereditary spastic paraplegia

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• hereditary spastic paraplegia 26

  Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 11 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 12-57631074-TG-T is Pathogenic according to our data. Variant chr12-57631074-TG-T is described in ClinVar as Pathogenic. ClinVar VariationId is 60523.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001478.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	B4GALNT1	NM_001478.5	MANE Select	c.395delC	p.Pro132GlnfsTer7	frameshift	Exon 4 of 11	NP_001469.1
	B4GALNT1	NM_001413967.1		c.395delC	p.Pro132GlnfsTer7	frameshift	Exon 4 of 11	NP_001400896.1
	B4GALNT1	NM_001413968.1		c.395delC	p.Pro132GlnfsTer7	frameshift	Exon 4 of 11	NP_001400897.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	B4GALNT1	ENST00000341156.9	TSL:1 MANE Select	c.395delC	p.Pro132GlnfsTer7	frameshift	Exon 4 of 11	ENSP00000341562.4
	B4GALNT1	ENST00000550764.5	TSL:1	c.395delC	p.Pro132GlnfsTer7	frameshift	Exon 4 of 6	ENSP00000450303.1
	B4GALNT1	ENST00000418555.6	TSL:2	c.230delC	p.Pro77GlnfsTer7	frameshift	Exon 3 of 10	ENSP00000401601.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000403 AC: 1 AN: 248064 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000291

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000343 AC: 5 AN: 1459636 Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3 AN XY: 725956

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.0000449 AC: 2 AN: 44582

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25882

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86044

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52854

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5740

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111056

Other (OTH) AF: 0.0000497 AC: 3 AN: 60304

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Hereditary spastic paraplegia 26 Pathogenic:1

Jul 11, 2013

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.1
Mutation Taster		=2/198	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs766591558; hg19: chr12-58024857;