rs786200938

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1PS1_ModeratePM2PP5_Moderate

The NM_080605.4(B3GALT6):​c.1A>C​(p.Met1?) variant causes a initiator codon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000048 in 834,202 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

B3GALT6
NM_080605.4 initiator_codon

Scores

5
1
10

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 2.03
Variant links:
Genes affected
B3GALT6 (HGNC:17978): (beta-1,3-galactosyltransferase 6) The enzyme encoded by this intronless gene is a beta-1,3-galactosyltransferase found in the medial Golgi apparatus, where it catalyzes the transfer of galactose from UDP-galactose to substrates containing a terminal beta-linked galactose moiety. The encoded enzyme has a particular affinity for galactose-beta-1,4-xylose found in the linker region of glycosamines. This enzyme is required for glycosaminoglycan synthesis. [provided by RefSeq, Jun 2013]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PVS1
Start lost variant, next in-frame start position is after 7 pathogenic variants. Next in-frame start position is after 123 CDS bases. Genomic position: 1232401. Lost 0.124 part of the original CDS.
PS1
Another start lost variant in NM_080605.4 (B3GALT6) was described as [Likely_pathogenic] in ClinVar as 1452181
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 1-1232279-A-C is Pathogenic according to our data. Variant chr1-1232279-A-C is described in ClinVar as [Pathogenic]. Clinvar id is 3250476.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
B3GALT6NM_080605.4 linkc.1A>C p.Met1? initiator_codon_variant Exon 1 of 1 ENST00000379198.5 NP_542172.2 Q96L58

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
B3GALT6ENST00000379198.5 linkc.1A>C p.Met1? initiator_codon_variant Exon 1 of 1 6 NM_080605.4 ENSP00000368496.2 Q96L58

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
AF:
0.00000479
AC:
4
AN:
834202
Hom.:
0
Cov.:
29
AF XY:
0.00000259
AC XY:
1
AN XY:
385392
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
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:
0.00000393
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33
Bravo
AF:
0.0000113

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Al-Gazali syndrome;C3809210:Ehlers-Danlos syndrome, spondylodysplastic type, 2;C4017377:Spondyloepimetaphyseal dysplasia with joint laxity, type 1, with or without fractures Pathogenic:1
Jun 26, 2024
Prenatal Genetic Diagnosis Laboratory, The Chinese University of Hong Kong
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change affects methionine residue at the initiation codon of the B3GALT6 mRNA (p.Met1?). Different varaints disrupting the initiator codon of B3GALT6 gene have been reported in multiple unrelated patients with Spondyloepimetaphyseal dysplasia with joint laxity (PMID: 23664117, ClinVar ID: 1067539, 1452181, 2151860). The same location with a different neucleotide change affecting the initiation codon, c.1A>G (p.Met1?), has been reported in four Japanese families with Spondyloepimetaphyseal dysplasia with joint laxity (PMID: 23664117). Functional study demonstrated the mutant B3GALT6 protein with c.1A>G had a molecular weight ~4 kD lower compared with the wildtype protein, suggesting the mutation in the initiation codon probably resulted in an N-terminal deletion of 41 amino acids (PMID: 23664117). The c.1A>C variant is currently not reported in any pateints nor in the gnomAD database (v2.1.1). Therefore, it is interpreted as pathogenic according to ACMG/AMP guidelines. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Benign
-0.057
T
BayesDel_noAF
Benign
-0.32
CADD
Benign
20
DANN
Benign
0.66
DEOGEN2
Benign
0.0027
T;T
Eigen
Benign
-0.50
Eigen_PC
Benign
-0.48
FATHMM_MKL
Pathogenic
0.97
D
LIST_S2
Uncertain
0.90
.;D
M_CAP
Pathogenic
0.96
D
MetaRNN
Pathogenic
0.80
D;D
MetaSVM
Benign
-1.1
T
PROVEAN
Benign
-0.62
.;N
REVEL
Benign
0.23
Sift
Pathogenic
0.0
.;D
Sift4G
Pathogenic
0.0
.;D
Polyphen
0.0
B;B
Vest4
0.71
MutPred
0.85
Loss of catalytic residue at M1 (P = 0.1551);Loss of catalytic residue at M1 (P = 0.1551);
MVP
0.56
ClinPred
0.98
D
GERP RS
2.6
Varity_R
0.95
gMVP
0.57

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs786200938; hg19: chr1-1167659; API