chr18-31627062-T-C

Position:

• chr18-31627062-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_004775.5(B4GALT6):​c.836A>G​(p.Lys279Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,428 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: B4GALT6 NM_004775.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.29

Genes affected

B4GALT6 (HGNC:929): (beta-1,4-galactosyltransferase 6) This gene is one of seven beta-1,4-galactosyltransferase (beta4GalT) genes in human. 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. This gene produces multiple protein isoforms - some of which are predicted to lack the N-terminal hydrophobic signal sequence and transmembrane domain. By sequence similarity, the beta4GalTs form four groups: beta4GalT1 and beta4GalT2, beta4GalT3 and beta4GalT4, beta4GalT5 and beta4GalT6, and beta4GalT7. The canonical enzyme encoded by this gene is a lactosylceramide synthase important for glycolipid biosynthesis. [provided by RefSeq, Jan 2020]

B4GALT6 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.17044014).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
B4GALT6	NM_004775.5	c.836A>G	p.Lys279Arg	missense_variant	7/9	ENST00000306851.10	NP_004766.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
B4GALT6	ENST00000306851.10	c.836A>G	p.Lys279Arg	missense_variant	7/9	1	NM_004775.5	ENSP00000306459.5
B4GALT6	ENST00000237019.11	c.719A>G	p.Lys240Arg	missense_variant	6/8	1		ENSP00000237019.7
B4GALT6	ENST00000383131.3	c.719A>G	p.Lys240Arg	missense_variant	6/8	1		ENSP00000372613.3
B4GALT6	ENST00000578114.1	n.737A>G		non_coding_transcript_exon_variant	3/5	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459428 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 725928

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 27, 2024

The c.836A>G (p.K279R) alteration is located in exon 7 (coding exon 7) of the B4GALT6 gene. This alteration results from a A to G substitution at nucleotide position 836, causing the lysine (K) at amino acid position 279 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	17
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.63	D;T;.
Eigen	Benign	-0.63
Eigen_PC	Benign	-0.52
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.81	T;T;T
M_CAP	Benign	0.0061	T
MetaRNN	Benign	0.17	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.1	L;.;.
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-1.8	N;N;N
REVEL	Benign	0.023
Sift	Benign	0.20	T;T;T
Sift4G	Benign	0.20	T;T;T
Polyphen		0.020	B;B;.
Vest4		0.21
MutPred		0.60		Loss of ubiquitination at K279 (P = 0.0255);.;.;
MVP		0.068
MPC		0.47
ClinPred		0.095	T
GERP RS		2.1
Varity_R		0.068
gMVP		0.74

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: rs1236373865; hg19: chr18-29207025;