1-1232972-C-T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PP2PP5BP4

The NM_080605.4(B3GALT6):c.694C>T(p.Arg232Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000102 in 1,563,436 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R232G) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000085 ( 0 hom. )

Consequence

B3GALT6
NM_080605.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:1

Conservation

PhyloP100: 1.16

Publications

9 publications found

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 Gene-Disease associations (from GenCC):

Ehlers-Danlos syndrome, spondylodysplastic type, 2
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P, Genomics England PanelApp
spondyloepimetaphyseal dysplasia with joint laxity, type 1, with or without fractures
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
spondyloepimetaphyseal dysplasia with joint laxity
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

B3GALT6 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 12 curated pathogenic missense variants (we use a threshold of 10). The gene has 3 curated benign missense variants. Gene score misZ: 1.2608 (below the threshold of 3.09). Trascript score misZ: -4.8226 (below the threshold of 3.09). GenCC associations: The gene is linked to spondyloepimetaphyseal dysplasia with joint laxity, type 1, with or without fractures, Ehlers-Danlos syndrome, spondylodysplastic type, 2, spondyloepimetaphyseal dysplasia with joint laxity.

PP5

Variant 1-1232972-C-T is Pathogenic according to our data. Variant chr1-1232972-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 60485.

BP4

Computational evidence support a benign effect (MetaRNN=0.19802365). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
B3GALT6	NM_080605.4 link	c.694C>T	p.Arg232Cys	missense_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 link	c.694C>T	p.Arg232Cys	missense_variant	Exon 1 of 1	6	NM_080605.4	ENSP00000368496.2

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152120

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000578

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000119

AC:

AN:

168310

AF XY:

0.0000107

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000151

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000850

AC:

AN:

1411198

Hom.:

Cov.:

AF XY:

0.0000100

AC XY:

AN XY:

699482

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32418

American (AMR)

AF:

0.00

AC:

AN:

40172

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25410

East Asian (EAS)

AF:

0.000295

AC:

AN:

37238

South Asian (SAS)

AF:

0.00

AC:

AN:

81696

European-Finnish (FIN)

AF:

0.0000276

AC:

AN:

36286

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4866

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1094426

Other (OTH)

AF:

0.00

AC:

AN:

58686

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152238

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74450

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41544

American (AMR)

AF:

0.00

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.000580

AC:

AN:

5176

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

67984

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.413

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000584

Hom.:

Bravo

AF:

0.0000151

ExAC

AF:

0.0000175

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

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

Pathogenic:1

Jan 12, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 232 of the B3GALT6 protein (p.Arg232Cys). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individuals with clinical features of spondyloepimetaphyseal dysplasia (PMID: 23664117, 32761602, 33631843, 35726512). ClinVar contains an entry for this variant (Variation ID: 60485). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt B3GALT6 protein function. Experimental studies have shown that this missense change affects B3GALT6 function (PMID: 23664117, 29443383). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

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

- -

not provided

Uncertain:1

May 23, 2019

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 25126564, 27871115, 28346368, 29443383, 26582078, 23903953, 23664117, 28306225) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.42

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.39

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.012

T;T

Eigen

Uncertain

0.26

Eigen_PC

Uncertain

0.22

FATHMM_MKL

Benign

0.57

LIST_S2

Uncertain

0.87

.;D

M_CAP

Pathogenic

0.75

MetaRNN

Benign

0.20

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.92

L;L

PhyloP100

1.2

PrimateAI

Uncertain

0.78

PROVEAN

Benign

-2.1

.;N

REVEL

Benign

0.23

Sift

Benign

0.068

.;T

Sift4G

Uncertain

0.054

.;T

Polyphen

0.98

D;D

Vest4

0.75

MutPred

0.55

Loss of MoRF binding (P = 0.0548);Loss of MoRF binding (P = 0.0548);

MVP

0.68

MPC

2.2

ClinPred

0.65

GERP RS

3.0

Varity_R

0.26

gMVP

0.65

Mutation Taster

=85/15

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over