20-49642499-C-A

Variant names:

• chr20-49642499-C-A
• rs201896811
• NM_004776.4:c.575G>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_004776.4(B4GALT5):​c.575G>T​(p.Arg192Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,564 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R192H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: B4GALT5 NM_004776.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.17
• Publications: 0 publications found

Genes affected

B4GALT5 (HGNC:928): (beta-1,4-galactosyltransferase 5) 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. The function of the enzyme encoded by this gene is not clear. This gene was previously designated as B4GALT4 but was renamed to B4GALT5. In the literature it is also referred to as beta4GalT2. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.824

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004776.4. 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
	B4GALT5	NM_004776.4	MANE Select	c.575G>T	p.Arg192Leu	missense	Exon 5 of 9	NP_004767.1	O43286

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	B4GALT5	ENST00000371711.4	TSL:1 MANE Select	c.575G>T	p.Arg192Leu	missense	Exon 5 of 9	ENSP00000360776.4	O43286
	B4GALT5	ENST00000921904.1		c.461G>T	p.Arg154Leu	missense	Exon 4 of 8	ENSP00000591963.1
	B4GALT5	ENST00000921905.1		c.575G>T	p.Arg192Leu	missense	Exon 5 of 8	ENSP00000591964.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461564 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727090

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33460

American (AMR) AF: 0.00 AC: 0 AN: 44686

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39688

South Asian (SAS) AF: 0.00 AC: 0 AN: 86236

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53396

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111816

Other (OTH) AF: 0.00 AC: 0 AN: 60384

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.59
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.22	T
Eigen	Uncertain	0.30
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.048	D
MetaRNN	Pathogenic	0.82	D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	2.0	M
PhyloP100		6.2
PrimateAI	Uncertain	0.63	T
PROVEAN	Uncertain	-2.8	D
REVEL	Benign	0.27
Sift	Benign	0.21	T
Sift4G	Benign	0.20	T
Polyphen		0.62	P
Vest4		0.83
MutPred		0.71		Loss of solvent accessibility (P = 0.0299)
MVP		0.22
MPC		2.4
ClinPred		0.96	D
GERP RS		4.8
Varity_R		0.22
gMVP		0.90
Mutation Taster		=21/79	disease causing

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: rs201896811; hg19: chr20-48259036;