Variant 1-1232279-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_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

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:4

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]

B3GALT6 links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PVS1

Start lost variant, no new inframe start found.

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/exons	MANE	Protein	UniProt
B3GALT6	NM_080605.4 linkuse as main transcript	c.1A>G	p.Met1?	start_lost	1/1	ENST00000379198.5	NP_542172.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
B3GALT6	ENST00000379198.5 linkuse as main transcript	c.1A>G	p.Met1?	start_lost	1/1		NM_080605.4	ENSP00000368496	P1

Frequencies

GnomAD3 genomes

AF:

0.0000416

AC:

AN:

144262

Hom.:

Cov.:

show subpopulations

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:

AN:

834202

Hom.:

Cov.:

AF XY:

0.00000778

AC XY:

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:

0.000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000918

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000485

AC:

AN:

144378

Hom.:

Cov.:

AF XY:

0.0000427

AC XY:

AN XY:

70306

show subpopulations

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

LINK: link

Submissions by phenotype

B3GALT6-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 10, 2023

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

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jan 07, 2023

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

Pathogenic, no assertion criteria provided

literature only

OMIM

Jun 06, 2013

- -

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

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 22, 2022

Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that disruption of the initiator codon affects B3GALT6 function (PMID: 23664117). ClinVar contains an entry for this variant (Variation ID: 60484). Disruption of the initiator codon has been observed in individuals with spondyloepimetaphyseal dysplasia (PMID: 23664117). This variant is present in population databases (rs786200938, gnomAD 0.007%). This sequence change affects the initiator methionine of the B3GALT6 mRNA. The next in-frame methionine is located at codon 42. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Uncertain

0.034

BayesDel_noAF

Benign

-0.19

CADD

Benign

DANN

Benign

0.72

DEOGEN2

Benign

0.0072

T;T

Eigen

Benign

-0.48

Eigen_PC

Benign

-0.46

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.90

.;D

M_CAP

Pathogenic

0.97

MetaRNN

Pathogenic

0.87

D;D

MetaSVM

Benign

-1.1

MutationTaster

Benign

1.0

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

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

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

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over