rs786200938

Variant names:

• chr1-1232279-A-C
• rs786200938
• NM_080605.4:c.1A>C

Your query was ambiguous. Multiple possible variants found:

• chr1-1232279-A-C
• chr1-1232279-A-G
• chr1-1232279-A-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1 PS1_Moderate PM2 PP5_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
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 2.03

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]

SDF4 (HGNC:24188): (stromal cell derived factor 4) This gene encodes a stromal cell derived factor that is a member of the CREC protein family. The encoded protein contains six EF-hand motifs and calcium-binding motifs. This protein localizes to the Golgi lumen and may be involved in regulating calcium dependent cellular activities. [provided by RefSeq, Sep 2011]

ACMG classification

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 42 codons. Genomic position: 1232402. Lost 0.125 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
B3GALT6	NM_080605.4	c.1A>C	p.Met1?	initiator_codon_variant	Exon 1 of 1	ENST00000379198.5	NP_542172.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
B3GALT6	ENST00000379198.5	c.1A>C	p.Met1?	initiator_codon_variant	Exon 1 of 1	6	NM_080605.4	ENSP00000368496.2
SDF4	ENST00000263741.12	c.-562T>G		upstream_gene_variant		1		ENSP00000263741.8
SDF4	ENST00000465727.5	n.-541T>G		upstream_gene_variant		2		ENSP00000435962.1

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

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

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

Other links and lift over

dbSNP: rs786200938; hg19: chr1-1167659;