chr1-1232295-G-A

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 1P and 7B. PP2BP4_ModerateBS1_SupportingBS2

The NM_080605.4(B3GALT6):c.17G>A(p.Arg6Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000722 in 981,976 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R6W) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00040 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00078 ( 2 hom. )

Consequence

B3GALT6
NM_080605.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:8O:1

Conservation

PhyloP100: 0.616

Publications

0 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: Likely_benign. The variant received -6 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.

BP4

Computational evidence support a benign effect (MetaRNN=0.15255421).

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000397 (58/146176) while in subpopulation NFE AF = 0.00076 (50/65780). AF 95% confidence interval is 0.000592. There are 0 homozygotes in GnomAd4. There are 28 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
B3GALT6	NM_080605.4 link	c.17G>A	p.Arg6Gln	missense_variant	Exon 1 of 1	ENST00000379198.5	NP_542172.2	Q96L58

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
B3GALT6	ENST00000379198.5 link	c.17G>A	p.Arg6Gln	missense_variant	Exon 1 of 1	6	NM_080605.4	ENSP00000368496.2		Q96L58

Frequencies

GnomAD3 genomes

AF:

0.000397

AC:

AN:

146176

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000147

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000680

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000120

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000760

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.000779

AC:

651

AN:

835800

Hom.:

Cov.:

AF XY:

0.000829

AC XY:

320

AN XY:

386226

show subpopulations

African (AFR)

AF:

0.0000633

AC:

AN:

15810

American (AMR)

AF:

0.00

AC:

AN:

1060

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

5198

East Asian (EAS)

AF:

0.00

AC:

AN:

3668

South Asian (SAS)

AF:

0.00

AC:

AN:

17282

European-Finnish (FIN)

AF:

0.00

AC:

AN:

406

Middle Eastern (MID)

AF:

0.00

AC:

AN:

1630

European-Non Finnish (NFE)

AF:

0.000836

AC:

638

AN:

763334

Other (OTH)

AF:

0.000438

AC:

AN:

27412

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

129

172

215

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

128

160

<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:

0.000397

AC:

AN:

146176

Hom.:

Cov.:

AF XY:

0.000394

AC XY:

AN XY:

71116

show subpopulations

African (AFR)

AF:

0.000147

AC:

AN:

40812

American (AMR)

AF:

0.0000680

AC:

AN:

14714

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3394

East Asian (EAS)

AF:

0.00

AC:

AN:

5082

South Asian (SAS)

AF:

0.00

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.000120

AC:

AN:

8342

Middle Eastern (MID)

AF:

0.00

AC:

AN:

306

European-Non Finnish (NFE)

AF:

0.000760

AC:

AN:

65780

Other (OTH)

AF:

0.00

AC:

AN:

2018

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

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:

0.000216

Hom.:

Bravo

AF:

0.000400

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:8Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:4Other:1

Jul 07, 2021

Revvity Omics, Revvity

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 26, 2024

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In silico analysis indicates that this missense variant does not alter protein structure/function; Has been reported in an individual with TAA (PMID: 35830949); This variant is associated with the following publications: (PMID: 35830949) -

GenomeConnect, ClinGen

Significance:not provided

Review Status:no classification provided

Collection Method:phenotyping only

Variant classified as Uncertain significance and reported on 12-15-2022 by GeneDx. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

Nov 01, 2020

CeGaT Center for Human Genetics Tuebingen

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 12, 2023

Mayo Clinic Laboratories, Mayo Clinic

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

BP4, PM5 -

not specified

Uncertain:1

Apr 14, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: B3GALT6 c.17G>A (p.Arg6Gln) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The frequency data for this variant in gnomAD is considered unreliable, as metrics indicate poor data quality at this position. To our knowledge, no occurrence of c.17G>A in individuals affected with Spondyloepimetaphyseal dysplasia with joint laxity, type 1, with or without fractures and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 429685). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Al-Gazali syndrome;C3809210:Ehlers-Danlos syndrome, spondylodysplastic type, 2;C4017377:Spondyloepimetaphyseal dysplasia with joint laxity, type 1, with or without fractures

Uncertain:1

Jul 21, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inborn genetic diseases

Uncertain:1

Aug 20, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.17G>A (p.R6Q) alteration is located in exon 1 (coding exon 1) of the B3GALT6 gene. This alteration results from a G to A substitution at nucleotide position 17, causing the arginine (R) at amino acid position 6 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

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

Uncertain:1

Oct 13, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 6 of the B3GALT6 protein (p.Arg6Gln). This variant is present in population databases (no rsID available, gnomAD 0.05%). This variant has not been reported in the literature in individuals affected with B3GALT6-related conditions. ClinVar contains an entry for this variant (Variation ID: 429685). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.55

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.0093

T;T

Eigen

Benign

-0.41

Eigen_PC

Benign

-0.43

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.61

.;T

M_CAP

Pathogenic

0.55

MetaRNN

Benign

0.15

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.5

L;L

PhyloP100

0.62

PrimateAI

Pathogenic

0.84

PROVEAN

Benign

-0.92

.;N

REVEL

Benign

0.058

Sift

Benign

0.097

.;T

Sift4G

Benign

0.11

.;T

Polyphen

0.95

P;P

Vest4

0.061

MVP

0.61

MPC

1.1

ClinPred

0.32

GERP RS

2.5

PromoterAI

-0.0073

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.0

Varity_R

0.14

gMVP

0.48

Mutation Taster

=89/11

polymorphism

(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