1-1232281-G-A

Variant names:

• chr1-1232281-G-A
• NM_080605.4:c.3G>A

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.3G>A​(p.Met1?) variant causes a start lost change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: B3GALT6 NM_080605.4 start_lost
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 4.79

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 1-1232281-G-A is Pathogenic according to our data. Variant chr1-1232281-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 2151860.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.3G>A	p.Met1?	start_lost	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.3G>A	p.Met1?	start_lost	Exon 1 of 1	6	NM_080605.4	ENSP00000368496.2
SDF4	ENST00000263741.12	c.-564C>T		upstream_gene_variant		1		ENSP00000263741.8
SDF4	ENST00000465727.5	n.-543C>T		upstream_gene_variant		2		ENSP00000435962.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Spondyloepimetaphyseal dysplasia with joint laxity;C3809210:Ehlers-Danlos syndrome, spondylodysplastic type, 2 Pathogenic:1

Nov 04, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects the initiator methionine of the B3GALT6 mRNA. The next in-frame methionine is located at codon 42. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the gnomAD database. Disruption of the initiator codon has been observed in individuals with B3GALT6-related conditions (PMID: 23664117, 29931299). ClinVar contains an entry for this variant (Variation ID: 2151860). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that disruption of the initiator codon affects B3GALT6 function (PMID: 23664117). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Benign	-0.13
CADD	Uncertain	24
DANN	Benign	0.94
DEOGEN2	Benign	0.0066	T;T
Eigen	Benign	-0.28
Eigen_PC	Benign	-0.23
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.90	.;D
M_CAP	Pathogenic	0.98	D
MetaRNN	Pathogenic	0.96	D;D
MetaSVM	Benign	-0.97	T
PROVEAN	Benign	-1.0	.;N
REVEL	Benign	0.24
Sift	Pathogenic	0.0	.;D
Sift4G	Pathogenic	0.0	.;D
Polyphen		0.063	B;B
Vest4		0.77
MutPred		0.84		Loss of disorder (P = 0.0562);Loss of disorder (P = 0.0562);
MVP		0.64
ClinPred		1.0	D
GERP RS		3.7
Varity_R		0.96
gMVP		0.67

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: chr1-1167661;