12-57629105-G-T

Variant names:

• chr12-57629105-G-T
• rs368334961
• NM_001478.5:c.754C>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001478.5(B4GALNT1):​c.754C>A​(p.Arg252Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000138 in 1,447,144 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R252H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: B4GALNT1 NM_001478.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.84
• Publications: 2 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2442264).

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.754C>A	p.Arg252Ser	missense	Exon 7 of 11	NP_001469.1
	B4GALNT1	NM_001413967.1		c.754C>A	p.Arg252Ser	missense	Exon 7 of 11	NP_001400896.1
	B4GALNT1	NM_001413968.1		c.754C>A	p.Arg252Ser	missense	Exon 7 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.754C>A	p.Arg252Ser	missense	Exon 7 of 11	ENSP00000341562.4
	B4GALNT1	ENST00000418555.6	TSL:2	c.589C>A	p.Arg197Ser	missense	Exon 6 of 10	ENSP00000401601.2
	B4GALNT1	ENST00000549391.5	TSL:3	n.*17C>A		non_coding_transcript_exon	Exon 4 of 6	ENSP00000447750.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000405 AC: 1 AN: 246612 AF XY: 0.00000751

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000896

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1447144 Hom.: 0 Cov.: 32 AF XY: 0.00000139 AC XY: 1 AN XY: 717088

African (AFR) AF: 0.00 AC: 0 AN: 33174

American (AMR) AF: 0.00 AC: 0 AN: 43870

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25780

East Asian (EAS) AF: 0.00 AC: 0 AN: 39344

South Asian (SAS) AF: 0.00 AC: 0 AN: 85176

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53188

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5718

European-Non Finnish (NFE) AF: 0.00000182 AC: 2 AN: 1101184

Other (OTH) AF: 0.00 AC: 0 AN: 59710

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Spastic paraplegia Uncertain:1

Mar 23, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt B4GALNT1 protein function. This sequence change replaces arginine, which is basic and polar, with serine, which is neutral and polar, at codon 252 of the B4GALNT1 protein (p.Arg252Ser). 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 variant has not been reported in the literature in individuals affected with B4GALNT1-related conditions. ClinVar contains an entry for this variant (Variation ID: 2417393). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.45
CADD	Uncertain	24
DANN	Benign	0.94
DEOGEN2	Benign	0.35	T
Eigen	Benign	-0.060
Eigen_PC	Benign	0.068
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.0055	T
MetaRNN	Benign	0.24	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.7	L
PhyloP100		3.8
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-0.60	N
REVEL	Benign	0.040
Sift	Benign	0.57	T
Sift4G	Benign	0.63	T
Polyphen		0.65	P
Vest4		0.52
MutPred		0.42		Gain of catalytic residue at P256 (P = 0)
MVP		0.28
MPC		0.27
ClinPred		0.57	D
GERP RS		4.3
PromoterAI		0.022	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.52
gMVP		0.59
Mutation Taster		=90/10	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs368334961; hg19: chr12-58022888;