rs149670131

chr12-57629131-T-C

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BS1_Supporting

The NM_001478.5(B4GALNT1):c.728A>G(p.Glu243Gly) variant causes a missense change. The variant allele was found at a frequency of 0.000484 in 1,595,116 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 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. E243K) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00057 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00047 (1 hom.)
• Consequence: B4GALNT1 NM_001478.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 4.20

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 Likely_benign. Variant got -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.01669401).
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000571 (87/152254) while in subpopulation SAS AF= 0.00187 (9/4816). AF 95% confidence interval is 0.000975. There are 0 homozygotes in gnomad4. There are 49 alleles in male gnomad4 subpopulation. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
B4GALNT1	NM_001478.5	c.728A>G	p.Glu243Gly	missense_variant	7/11	ENST00000341156.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
B4GALNT1	ENST00000341156.9	c.728A>G	p.Glu243Gly	missense_variant	7/11	1	NM_001478.5	P1

Frequencies

GnomAD3 genomes AF: 0.000572 AC: 87 AN: 152136 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00187

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000926

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.000619 AC: 151 AN: 244068 Hom.: 0 AF XY: 0.000645 AC XY: 85 AN XY: 131868

Gnomad AFR exome AF: 0.000186

Gnomad AMR exome AF: 0.000120

Gnomad ASJ exome AF: 0.00147

Gnomad EAS exome AF: 0.0000550

Gnomad SAS exome AF: 0.00107

Gnomad FIN exome AF: 0.0000470

Gnomad NFE exome AF: 0.000859

Gnomad OTH exome AF: 0.000335

GnomAD4 exome AF: 0.000475 AC: 685 AN: 1442862 Hom.: 1 Cov.: 32 AF XY: 0.000489 AC XY: 349 AN XY: 714268

Gnomad4 AFR exome AF: 0.0000908

Gnomad4 AMR exome AF: 0.000207

Gnomad4 ASJ exome AF: 0.000899

Gnomad4 EAS exome AF: 0.0000255

Gnomad4 SAS exome AF: 0.00155

Gnomad4 FIN exome AF: 0.000245

Gnomad4 NFE exome AF: 0.000418

Gnomad4 OTH exome AF: 0.000638

GnomAD4 genome AF: 0.000571 AC: 87 AN: 152254 Hom.: 0 Cov.: 33 AF XY: 0.000658 AC XY: 49 AN XY: 74456

Gnomad4 AFR AF: 0.000217

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00187

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000926

Gnomad4 OTH AF: 0.000945

Alfa AF: 0.000709 Hom.: 0

Bravo AF: 0.000442

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00151 AC: 13

ExAC AF: 0.000824 AC: 100

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Spastic paraplegia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jan 02, 2024

This sequence change replaces glutamic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 243 of the B4GALNT1 protein (p.Glu243Gly). This variant is present in population databases (rs149670131, gnomAD 0.2%), and has an allele count higher than expected for a pathogenic variant. 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: 458224). 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 with a negative predictive value of 80%. 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. -

Hereditary spastic paraplegia 26 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Sep 20, 2019

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.52
Cadd	Benign	19
Dann	Uncertain	0.99
DEOGEN2	Benign	0.35	T;.
Eigen	Benign	-0.38
Eigen_PC	Benign	-0.20
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.76	T;T
M_CAP	Benign	0.0067	T
MetaRNN	Benign	0.017	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.93	L;.
MutationTaster	Benign	0.90	D;D
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-2.0	N;N
REVEL	Benign	0.056
Sift	Benign	0.27	T;T
Sift4G	Benign	0.40	T;T
Polyphen		0.0010	B;.
Vest4		0.22
MVP		0.31
MPC		0.23
ClinPred		0.019	T
GERP RS		2.8
Varity_R		0.11
gMVP		0.76

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

Publications

LitVar

Other links and lift over

dbSNP: rs149670131; hg19: chr12-58022914;