9-33125806-T-C

Variant names:

• chr9-33125806-T-C
• rs10758189
• NM_001497.4:c.649-5200A>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.649-5200A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.372 in 151,962 control chromosomes in the GnomAD database, including 11,216 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 0.37 (11216 hom., cov: 31)
• Consequence: B4GALT1 NM_001497.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.379
• Publications: 18 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=-0.84).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.577 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001497.4. 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
	B4GALT1	NM_001497.4	MANE Select	c.649-5200A>G		intron	N/A	NP_001488.2
	B4GALT1	NM_001378495.1		c.610-5200A>G		intron	N/A	NP_001365424.1
	B4GALT1	NM_001378496.1		c.649-5200A>G		intron	N/A	NP_001365425.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	B4GALT1	ENST00000379731.5	TSL:1 MANE Select	c.649-5200A>G		intron	N/A	ENSP00000369055.4
	B4GALT1	ENST00000535206.6	TSL:1	c.648+9383A>G		intron	N/A	ENSP00000440341.1
	B4GALT1	ENST00000718311.1		n.727+2230A>G		intron	N/A	ENSP00000520749.1

Frequencies

GnomAD3 genomes AF: 0.372 AC: 56451 AN: 151844 Hom.: 11210 Cov.: 31

Gnomad AFR AF: 0.493

Gnomad AMI AF: 0.272

Gnomad AMR AF: 0.301

Gnomad ASJ AF: 0.385

Gnomad EAS AF: 0.595

Gnomad SAS AF: 0.388

Gnomad FIN AF: 0.257

Gnomad MID AF: 0.351

Gnomad NFE AF: 0.315

Gnomad OTH AF: 0.351

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

GnomAD4 genome AF: 0.372 AC: 56484 AN: 151962 Hom.: 11216 Cov.: 31 AF XY: 0.370 AC XY: 27467 AN XY: 74268

African (AFR) AF: 0.493 AC: 20399 AN: 41404

American (AMR) AF: 0.300 AC: 4595 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.385 AC: 1334 AN: 3464

East Asian (EAS) AF: 0.595 AC: 3068 AN: 5158

South Asian (SAS) AF: 0.389 AC: 1873 AN: 4816

European-Finnish (FIN) AF: 0.257 AC: 2710 AN: 10564

Middle Eastern (MID) AF: 0.330 AC: 97 AN: 294

European-Non Finnish (NFE) AF: 0.315 AC: 21424 AN: 67948

Other (OTH) AF: 0.349 AC: 736 AN: 2110

Alfa AF: 0.367 Hom.: 6825

Bravo AF: 0.378

Asia WGS AF: 0.454 AC: 1574 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	7.4
DANN	Benign	0.70
PhyloP100		0.38
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: rs10758189; hg19: chr9-33125804; COSMIC: COSV65708811;