NM_080605.4:c.1A>G

Variant names:

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

Variant summary

Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PVS1 PS1_Moderate PM2 PP5_Very_Strong

The NM_080605.4(B3GALT6):​c.1A>G​(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000164 in 978,580 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: 𝑓 0.000048 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: B3GALT6 NM_080605.4 start_lost
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• 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]

ACMG classification

Verdict is Pathogenic. Variant got 20 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-G is Pathogenic according to our data. Variant chr1-1232279-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 60484.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
B3GALT6	NM_080605.4	c.1A>G	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.1A>G	p.Met1?	start_lost	Exon 1 of 1	6	NM_080605.4	ENSP00000368496.2

Frequencies

GnomAD3 genomes AF: 0.0000416 AC: 6 AN: 144262 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000253

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000683

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000611

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000108 AC: 9 AN: 834202 Hom.: 0 Cov.: 29 AF XY: 0.00000778 AC XY: 3 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: 0.000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000918

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000485 AC: 7 AN: 144378 Hom.: 0 Cov.: 33 AF XY: 0.0000427 AC XY: 3 AN XY: 70306

Gnomad4 AFR AF: 0.0000504

Gnomad4 AMR AF: 0.0000682

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000611

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000416

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

B3GALT6-related disorder Pathogenic:1

Nov 10, 2023

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The B3GALT6 c.1A>G variant is predicted to disrupt the translation initiation site (Start Loss). This variant has been previously reported in the heterozygous compound state in individuals with spondyloepimetaphyseal dysplasia with joint laxity type I and Ehlers-Danlos syndrome, progeroid form (Nakajima et al 2013. PubMed ID: 23664117). In vitro functional studies found that this variant yields a shorter protein compared to the wild type form; and, is localized in the cytoplasm and nucleus while the wild type is found in the Golgi apparatus (Nakajima et al 2013. PubMed ID: 23664117). This variant is reported in 0.0076% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/1-1167659-A-G). This variant is interpreted as pathogenic. -

not provided Pathogenic:1

Jan 07, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Reported in five Japanese patients diagnosed with spondyloepimetaphyseal dysplasia with joint laxity type 1 (currently referred to as spEDS), four of whom harbored an additional missense variant in the B3GALT6 gene (Nakajima et al.,2013); Initiation codon variant in a gene for which loss of function is a known mechanism of disease; an alternate in-frame possible start codon is located at codon 42; Published functional studies demonstrate a damaging effect as this variant results in a reduced molecular weight and mislocalization of the mutant protein compared to wild type, suggesting the c.1 A>G variant results in the use of an alternate initiation codon at c.124, causing an N-terminal deletion of 41 amino acids (Nakajima et al., 2013); Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 23664117, 31980526, 34426522) -

Spondyloepimetaphyseal dysplasia with joint laxity, type 1, with or without fractures Pathogenic:1

Jun 06, 2013

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

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

Aug 31, 2024

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. This variant is present in population databases (rs786200938, gnomAD 0.007%). Disruption of the initiator codon has been observed in individuals with spondyloepimetaphyseal dysplasia (PMID: 23664117). ClinVar contains an entry for this variant (Variation ID: 60484). Algorithms developed to predict the effect of variants on gene product 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	Uncertain	0.034	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	20
DANN	Benign	0.72
DEOGEN2	Benign	0.0072	T;T
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.46
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.90	.;D
M_CAP	Pathogenic	0.97	D
MetaRNN	Pathogenic	0.87	D;D
MetaSVM	Benign	-1.1	T
PROVEAN	Benign	-1.1	.;N
REVEL	Benign	0.19
Sift	Pathogenic	0.0	.;D
Sift4G	Pathogenic	0.0	.;D
Polyphen		0.063	B;B
Vest4		0.77
MutPred		0.89		Gain of relative solvent accessibility (P = 0.0166);Gain of relative solvent accessibility (P = 0.0166);
MVP		0.61
ClinPred		0.97	D
GERP RS		2.6
Varity_R		0.94
gMVP		0.71

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;