NM_001497.4:c.259C>T

Variant names:

• chr9-33166911-G-A
• rs149181384
• NM_001497.4:c.259C>T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_001497.4(B4GALT1):​c.259C>T​(p.Pro87Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000314 in 1,576,632 control chromosomes in the GnomAD database, including 1 homozygotes. 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0016 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00018 (0 hom.)
• Consequence: B4GALT1 NM_001497.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 0.894
• Publications: 2 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: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005222708).
• BP6: Variant 9-33166911-G-A is Benign according to our data. Variant chr9-33166911-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 719722.

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.259C>T	p.Pro87Ser	missense	Exon 1 of 6	NP_001488.2
	B4GALT1	NM_001378495.1		c.220C>T	p.Pro74Ser	missense	Exon 1 of 6	NP_001365424.1	P15291-2
	B4GALT1	NM_001378496.1		c.259C>T	p.Pro87Ser	missense	Exon 1 of 5	NP_001365425.1	W6MEN3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	B4GALT1	ENST00000379731.5	TSL:1 MANE Select	c.259C>T	p.Pro87Ser	missense	Exon 1 of 6	ENSP00000369055.4	P15291-1
	B4GALT1	ENST00000535206.6	TSL:1	c.259C>T	p.Pro87Ser	missense	Exon 1 of 3	ENSP00000440341.1	Q86XA6
	B4GALT1	ENST00000860372.1		c.259C>T	p.Pro87Ser	missense	Exon 1 of 7	ENSP00000530431.1

Frequencies

GnomAD3 genomes AF: 0.00158 AC: 240 AN: 152234 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00564

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000284 AC: 53 AN: 186338 AF XY: 0.000233

Gnomad AFR exome AF: 0.00437

Gnomad AMR exome AF: 0.000140

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000122

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000178 AC: 254 AN: 1424282 Hom.: 0 Cov.: 31 AF XY: 0.000177 AC XY: 125 AN XY: 706454

African (AFR) AF: 0.00636 AC: 210 AN: 33010

American (AMR) AF: 0.000225 AC: 9 AN: 39946

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25524

East Asian (EAS) AF: 0.00 AC: 0 AN: 38732

South Asian (SAS) AF: 0.0000120 AC: 1 AN: 83654

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38440

Middle Eastern (MID) AF: 0.000185 AC: 1 AN: 5418

European-Non Finnish (NFE) AF: 0.00000727 AC: 8 AN: 1100292

Other (OTH) AF: 0.000422 AC: 25 AN: 59266

GnomAD4 genome AF: 0.00158 AC: 241 AN: 152350 Hom.: 1 Cov.: 33 AF XY: 0.00152 AC XY: 113 AN XY: 74498

African (AFR) AF: 0.00565 AC: 235 AN: 41592

American (AMR) AF: 0.000327 AC: 5 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68024

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.000303 Hom.: 0

Bravo AF: 0.00188

ESP6500AA AF: 0.00376 AC: 16

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000473 AC: 55

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	B4GALT1-congenital disorder of glycosylation (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.011	T
Eigen	Benign	-0.33
Eigen_PC	Benign	-0.31
FATHMM_MKL	Benign	0.092	N
LIST_S2	Benign	0.69	T
M_CAP	Benign	0.036	D
MetaRNN	Benign	0.0052	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	2.0	M
PhyloP100		0.89
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-0.41	N
REVEL	Benign	0.034
Sift	Benign	0.057	T
Sift4G	Benign	0.49	T
Polyphen		0.22	B
Vest4		0.24
MVP		0.67
MPC		0.49
ClinPred		0.022	T
GERP RS		2.9
PromoterAI		-0.050	Neutral
Varity_R		0.045
gMVP		0.42
Mutation Taster		=92/8	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: rs149181384; hg19: chr9-33166909;