chr9-33124874-T-C

Variant names:

• chr9-33124874-T-C
• rs12342831
• NM_001497.4:c.649-4268A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001497.4(B4GALT1):​c.649-4268A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.257 in 152,120 control chromosomes in the GnomAD database, including 5,394 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.26 (5394 hom., cov: 33)
• Consequence: B4GALT1 NM_001497.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0540
• Publications: 27 publications found

Genes affected

B4GALT1 (HGNC:924): (beta-1,4-galactosyltransferase 1) This gene is one of seven beta-1,4-galactosyltransferase (beta4GalT) genes. They encode type II membrane-bound glycoproteins that appear to have exclusive specificity for the donor substrate UDP-galactose; all transfer galactose in a beta1,4 linkage to similar acceptor sugars: GlcNAc, Glc, and Xyl. Each beta4GalT has a distinct function in the biosynthesis of different glycoconjugates and saccharide structures. As type II membrane proteins, they have an N-terminal hydrophobic signal sequence that directs the protein to the Golgi apparatus and which then remains uncleaved to function as a transmembrane anchor. By sequence similarity, the beta4GalTs form four groups: beta4GalT1 and beta4GalT2, beta4GalT3 and beta4GalT4, beta4GalT5 and beta4GalT6, and beta4GalT7. This gene is unique among the beta4GalT genes because it encodes an enzyme that participates both in glycoconjugate and lactose biosynthesis. For the first activity, the enzyme adds galactose to N-acetylglucosamine residues that are either monosaccharides or the nonreducing ends of glycoprotein carbohydrate chains. The second activity is restricted to lactating mammary tissues where the enzyme forms a heterodimer with alpha-lactalbumin to catalyze UDP-galactose + D-glucose <=> UDP + lactose. The two enzymatic forms result from alternate transcription initiation sites and post-translational processing. Two transcripts, which differ only at the 5' end, with approximate lengths of 4.1 kb and 3.9 kb encode the same protein. The longer transcript encodes the type II membrane-bound, trans-Golgi resident protein involved in glycoconjugate biosynthesis. The shorter transcript encodes a protein which is cleaved to form the soluble lactose synthase. [provided by RefSeq, Jul 2008]

B4GALT1 Gene-Disease associations (from GenCC):

• B4GALT1-congenital disorder of glycosylation

  Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.51 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
B4GALT1	NM_001497.4	c.649-4268A>G		intron_variant	Intron 2 of 5	ENST00000379731.5	NP_001488.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
B4GALT1	ENST00000379731.5	c.649-4268A>G		intron_variant	Intron 2 of 5	1	NM_001497.4	ENSP00000369055.4
B4GALT1	ENST00000535206.6	c.648+10315A>G		intron_variant	Intron 2 of 2	1		ENSP00000440341.1
B4GALT1	ENST00000718311.1	n.727+3162A>G		intron_variant	Intron 3 of 6			ENSP00000520749.1

Frequencies

GnomAD3 genomes AF: 0.257 AC: 39062 AN: 152002 Hom.: 5395 Cov.: 33

Gnomad AFR AF: 0.251

Gnomad AMI AF: 0.240

Gnomad AMR AF: 0.191

Gnomad ASJ AF: 0.304

Gnomad EAS AF: 0.527

Gnomad SAS AF: 0.342

Gnomad FIN AF: 0.213

Gnomad MID AF: 0.241

Gnomad NFE AF: 0.254

Gnomad OTH AF: 0.252

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.257 AC: 39075 AN: 152120 Hom.: 5394 Cov.: 33 AF XY: 0.257 AC XY: 19148 AN XY: 74370

African (AFR) AF: 0.251 AC: 10412 AN: 41490

American (AMR) AF: 0.191 AC: 2912 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.304 AC: 1055 AN: 3472

East Asian (EAS) AF: 0.527 AC: 2728 AN: 5178

South Asian (SAS) AF: 0.343 AC: 1654 AN: 4824

European-Finnish (FIN) AF: 0.213 AC: 2255 AN: 10574

Middle Eastern (MID) AF: 0.235 AC: 69 AN: 294

European-Non Finnish (NFE) AF: 0.254 AC: 17242 AN: 67988

Other (OTH) AF: 0.251 AC: 529 AN: 2108

Alfa AF: 0.257 Hom.: 20812

Bravo AF: 0.252

Asia WGS AF: 0.391 AC: 1356 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	4.2
DANN	Benign	0.64
PhyloP100		0.054
Mutation Taster		=100/0	polymorphism (auto)

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: rs12342831; hg19: chr9-33124872;