1-161175082-G-C

Variant names:

• chr1-161175082-G-C
• NM_003779.4:c.400C>G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_003779.4(B4GALT3):​c.400C>G​(p.Arg134Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. R134W) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: B4GALT3 NM_003779.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.24

Genes affected

B4GALT3 (HGNC:926): (beta-1,4-galactosyltransferase 3) 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 encodes an enzyme that may be mainly involved in the synthesis of the first N-acetyllactosamine unit of poly-N-acetyllactosamine chains. Multiple alternatively spliced transcript variants encoding the same protein have been found for this gene. [provided by RefSeq, Dec 2010]

PPOX (HGNC:9280): (protoporphyrinogen oxidase) This gene encodes the penultimate enzyme of heme biosynthesis, which catalyzes the 6-electron oxidation of protoporphyrinogen IX to form protoporphyrin IX. Mutations in this gene cause variegate porphyria, an autosomal dominant disorder of heme metabolism resulting from a deficiency in protoporphyrinogen oxidase, an enzyme located on the inner mitochondrial membrane. Alternatively spliced transcript variants encoding the same protein have been identified. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.984

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
B4GALT3	NM_003779.4	c.400C>G	p.Arg134Gly	missense_variant	Exon 4 of 8	ENST00000319769.10	NP_003770.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
B4GALT3	ENST00000319769.10	c.400C>G	p.Arg134Gly	missense_variant	Exon 4 of 8	1	NM_003779.4	ENSP00000320965.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.17
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.35	T;T;T
Eigen	Pathogenic	0.71
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.97	.;D;.
M_CAP	Benign	0.055	D
MetaRNN	Pathogenic	0.98	D;D;D
MetaSVM	Benign	-0.36	T
MutationAssessor	Pathogenic	3.5	H;H;H
PrimateAI	Uncertain	0.68	T
PROVEAN	Pathogenic	-6.3	D;.;D
REVEL	Uncertain	0.58
Sift	Uncertain	0.0010	D;.;D
Sift4G	Uncertain	0.0020	D;D;D
Polyphen		1.0	D;D;D
Vest4		0.96
MutPred		0.96		Loss of stability (P = 0.0461);Loss of stability (P = 0.0461);Loss of stability (P = 0.0461);
MVP		0.74
MPC		0.84
ClinPred		0.99	D
GERP RS		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.80
gMVP		0.96

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-161144872;