NM_001497.4:c.5G>C

Variant names:

• chr9-33167165-C-G
• rs1587756000
• NM_001497.4:c.5G>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001497.4(B4GALT1):​c.5G>C​(p.Arg2Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000208 in 1,445,410 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 (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: B4GALT1 NM_001497.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.288
• Publications: 0 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-AS1 (HGNC:49910): (B4GALT1 antisense RNA 1)

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.38467675).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	B4GALT1	NM_001497.4	MANE Select	c.5G>C	p.Arg2Thr	missense	Exon 1 of 6	NP_001488.2
	B4GALT1	NM_001378496.1		c.5G>C	p.Arg2Thr	missense	Exon 1 of 5	NP_001365425.1	W6MEN3
	B4GALT1	NM_001378497.1		c.5G>C	p.Arg2Thr	missense	Exon 1 of 3	NP_001365426.1	Q86XA6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	B4GALT1	ENST00000379731.5	TSL:1 MANE Select	c.5G>C	p.Arg2Thr	missense	Exon 1 of 6	ENSP00000369055.4	P15291-1
	B4GALT1	ENST00000535206.6	TSL:1	c.5G>C	p.Arg2Thr	missense	Exon 1 of 3	ENSP00000440341.1	Q86XA6
	B4GALT1	ENST00000860372.1		c.5G>C	p.Arg2Thr	missense	Exon 1 of 7	ENSP00000530431.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000208 AC: 3 AN: 1445410 Hom.: 0 Cov.: 31 AF XY: 0.00000139 AC XY: 1 AN XY: 718228

African (AFR) AF: 0.0000305 AC: 1 AN: 32840

American (AMR) AF: 0.00 AC: 0 AN: 43344

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25702

East Asian (EAS) AF: 0.00 AC: 0 AN: 39208

South Asian (SAS) AF: 0.00 AC: 0 AN: 85024

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48402

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5286

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1106034

Other (OTH) AF: 0.0000336 AC: 2 AN: 59570

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	B4GALT1-congenital disorder of glycosylation (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	21
DANN	Benign	0.95
DEOGEN2	Benign	0.011	T
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.16
FATHMM_MKL	Benign	0.52	D
LIST_S2	Benign	0.44	T
M_CAP	Pathogenic	0.65	D
MetaRNN	Benign	0.38	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.8	L
PhyloP100		0.29
PrimateAI	Pathogenic	0.92	D
PROVEAN	Benign	-0.49	N
REVEL	Benign	0.025
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.013	D
Polyphen		0.32	B
Vest4		0.27
MutPred		0.25		Loss of methylation at R2 (P = 0.0185)
MVP		0.77
MPC		0.83
ClinPred		0.64	D
GERP RS		2.6
PromoterAI		0.60	Over-expression
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.9
Varity_R		0.11
gMVP		0.74
Mutation Taster		=94/6	polymorphism

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: rs1587756000; hg19: chr9-33167163;