1-1232280-T-C

Variant summary

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

The NM_080605.4(B3GALT6):c.2T>C(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 0.0000143 in 978,268 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 0.000056 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000072 ( 0 hom. )

Consequence

B3GALT6
NM_080605.4 start_lost

Scores

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 1.18

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 14 ACMG points.

PVS1

Start lost variant, no new inframe start found.

PS1

Another start lost variant in NM_080605.4 (B3GALT6) was described as [Pathogenic] in ClinVar as 60484

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 1-1232280-T-C is Pathogenic according to our data. Variant chr1-1232280-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 1452181.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
B3GALT6	NM_080605.4 linkuse as main transcript	c.2T>C	p.Met1?	start_lost	1/1	ENST00000379198.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
B3GALT6	ENST00000379198.5 linkuse as main transcript	c.2T>C	p.Met1?	start_lost	1/1		NM_080605.4	P1

Frequencies

GnomAD3 genomes

AF:

0.0000555

AC:

AN:

144108

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000127

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000137

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:

0.00

Gnomad OTH

AF:

0.000506

GnomAD4 exome

AF:

0.00000719

AC:

AN:

834160

Hom.:

Cov.:

AF XY:

0.00000259

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:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000787

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000555

AC:

AN:

144108

Hom.:

Cov.:

AF XY:

0.0000855

AC XY:

AN XY:

70136

show subpopulations

Gnomad4 AFR

AF:

0.000127

Gnomad4 AMR

AF:

0.000137

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000506

Bravo

AF:

0.0000604

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

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

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Aug 17, 2023

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 (no rsID available, gnomAD 0.01%). Disruption of the initiator codon has been observed in individuals with spondyloepimetaphyseal dysplasia or Ehlers-Danlos syndrome (PMID: 23664117, 29931299). ClinVar contains an entry for this variant (Variation ID: 1452181). 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

BayesDel_noAF

Benign

-0.17

Cadd

Benign

Dann

Benign

0.68

DEOGEN2

Benign

0.0078

T;T

Eigen

Benign

-0.47

Eigen_PC

Benign

-0.47

FATHMM_MKL

Pathogenic

0.98

M_CAP

Pathogenic

0.96

MetaRNN

Pathogenic

0.97

D;D

MetaSVM

Benign

-1.0

MutationTaster

Benign

1.0

Polyphen

0.24

B;B

Vest4

0.60

MutPred

0.87

Loss of stability (P = 0.008);Loss of stability (P = 0.008);

MVP

0.50

ClinPred

0.97

GERP RS

2.4

Varity_R

0.93

gMVP

0.75

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