12-57629066-C-A

Variant names:

• chr12-57629066-C-A
• rs144922627
• NM_001478.5:c.793G>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001413981.1(B4GALNT1):​c.-195G>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000696 in 1,436,646 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: B4GALNT1 NM_001413981.1 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.48
• 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: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001413981.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	B4GALNT1	NM_001478.5	MANE Select	c.793G>T	p.Gly265Trp	missense	Exon 7 of 11	NP_001469.1	Q00973-1
	B4GALNT1	NM_001413981.1		c.-195G>T		5_prime_UTR_premature_start_codon_gain	Exon 8 of 12	NP_001400910.1
	B4GALNT1	NM_001413982.1		c.-195G>T		5_prime_UTR_premature_start_codon_gain	Exon 8 of 12	NP_001400911.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	B4GALNT1	ENST00000341156.9	TSL:1 MANE Select	c.793G>T	p.Gly265Trp	missense	Exon 7 of 11	ENSP00000341562.4	Q00973-1
	B4GALNT1	ENST00000882412.1		c.793G>T	p.Gly265Trp	missense	Exon 7 of 11	ENSP00000552471.1
	B4GALNT1	ENST00000954202.1		c.793G>T	p.Gly265Trp	missense	Exon 6 of 10	ENSP00000624261.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.96e-7 AC: 1 AN: 1436646 Hom.: 0 Cov.: 32 AF XY: 0.00000141 AC XY: 1 AN XY: 710440

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 32986

American (AMR) AF: 0.00 AC: 0 AN: 43112

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24886

East Asian (EAS) AF: 0.00 AC: 0 AN: 39268

South Asian (SAS) AF: 0.0000120 AC: 1 AN: 83494

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52806

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5658

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1095292

Other (OTH) AF: 0.00 AC: 0 AN: 59144

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Benign	-0.087	T
BayesDel_noAF	Benign	-0.36
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.84	D
Eigen	Benign	0.011
Eigen_PC	Benign	-0.15
FATHMM_MKL	Benign	0.50	N
LIST_S2	Benign	0.83	T
M_CAP	Benign	0.026	D
MetaRNN	Uncertain	0.62	D
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.7	M
PhyloP100		2.5
PrimateAI	Benign	0.42	T
PROVEAN	Uncertain	-3.6	D
REVEL	Benign	0.14
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.60
MutPred		0.52		Gain of catalytic residue at P263 (P = 0.0016)
MVP		0.42
MPC		0.82
ClinPred		1.0	D
GERP RS		2.8
PromoterAI		0.021	Neutral
Varity_R		0.18
gMVP		0.78
Mutation Taster		=94/6	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs144922627; hg19: chr12-58022849;