Variant 1-1232859-CGGGG-CGGGGG details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PVS1_StrongPM2PP5

The NM_080605.4(B3GALT6):c.588dupG(p.Arg197fs) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000145 in 1,533,176 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. R197R) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00016 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00014 ( 0 hom. )

Consequence

B3GALT6
NM_080605.4 frameshift

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:3

Conservation

PhyloP100: -8.47

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 Likely_pathogenic. Variant got 7 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 14 pathogenic variants in the truncated region.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 1-1232859-C-CG is Pathogenic according to our data. Variant chr1-1232859-C-CG is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 427130.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=3, Likely_pathogenic=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
B3GALT6	NM_080605.4 linkuse as main transcript	c.588dupG	p.Arg197fs	frameshift_variant	1/1	ENST00000379198.5	NP_542172.2	Q96L58

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
B3GALT6	ENST00000379198.5 linkuse as main transcript	c.588dupG	p.Arg197fs	frameshift_variant	1/1	6	NM_080605.4	ENSP00000368496.2		Q96L58

Frequencies

GnomAD3 genomes

AF:

0.000158

AC:

AN:

151792

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000968

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000386

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000206

Gnomad OTH

AF:

0.000958

GnomAD4 exome

AF:

0.000143

AC:

198

AN:

1381276

Hom.:

Cov.:

AF XY:

0.000142

AC XY:

AN XY:

684756

show subpopulations

Gnomad4 AFR exome

AF:

0.000104

Gnomad4 AMR exome

AF:

0.000409

Gnomad4 ASJ exome

AF:

0.0000419

Gnomad4 EAS exome

AF:

0.000145

Gnomad4 SAS exome

AF:

0.000182

Gnomad4 FIN exome

AF:

0.0000285

Gnomad4 NFE exome

AF:

0.000141

Gnomad4 OTH exome

AF:

0.000122

GnomAD4 genome

AF:

0.000158

AC:

AN:

151900

Hom.:

Cov.:

AF XY:

0.000148

AC XY:

AN XY:

74248

show subpopulations

Gnomad4 AFR

AF:

0.0000965

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000387

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000206

Gnomad4 OTH

AF:

0.000948

Bravo

AF:

0.000155

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:1Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 28, 2023	Frameshift variant in a single exon gene predicted to result in an altered/extended protein product, as the last 133 amino acids are lost and replaced with 245 incorrect amino acids; Observed with another variant on the opposite allele (in trans) in two related individuals with spEDS referred for genetic testing at GeneDx; Other frameshift variants have been reported in the Human Gene Mutation Database in association with spEDS, including one affecting the same residue and resulting in a premature termination codon 81 residues downstream (c.588delG, p.(Arg197AlafsX81)) (PMID: 23664117, 34529350, 29931299); This variant is associated with the following publications: (PMID: 34529350, 23664117, 29931299) -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Oct 13, 2023	PVS1_strong -

Al-Gazali syndrome

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

DASA

Feb 05, 2022

The c.588dup;p.(Arg197Alafs*246) is a null frameshift variant (NMD) in the B3GALT6 gene and predicts alteration of the nonsense-mediate decay - NMD is present in a relevant exon to the transcript - PVS1_strong. This variant is not present in population databases (rs533071750, gnomAD; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2. In summary, the currently available evidence indicates that the variant is likely pathogenic. -

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

Uncertain:1

Uncertain significance, criteria provided, single submitter

curation

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Jan 25, 2023

The heterozygous p.Arg197fsAlaTer246 variant in B3GALT6 was identified by our study, in the compound heterozygous state with a variant of uncertain significance (ClinVar Variation ID: 986387), in two siblings with spondyloepimetaphyseal dysplasia with joint laxity, type 1. Familial genome analysis revealed that this variant was in trans with a variant of uncertain significance (ClinVar Variation ID: 986387). The p.Arg197fsAlaTer246 version in B3GALT6 has been previously reported in one individual with spondyloepimetaphyseal dysplasia with joint laxity, type 1, but has been identified in 0.04% (10/22694) of Latino/Admixed American chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs533071750). Although this variant has been seen in the general population in a heterozygous state, its frequency is not high enough to rule out a pathogenic role. The affected individual previously reported was a compound heterozygote who carried a variant of uncertain significance in trans (PMID: 34529350, ClinVar ID: 60493), which increases the likelihood that the p.Arg197fsAlaTer246 variant is pathogenic. This variant is predicted to cause a frameshift, which alters the protein‚Äôs amino acid sequence beginning at position 197 and leads to a premature termination codon 246 amino acids downstream. This gene is a single exon gene and is more likely to escape nonsense mediated decay (NMD) and result in a truncated protein. While there is some evidence to suggest that loss of function of the B3GALT6 gene is a disease mechanism in autosomal recessive spondyloepimetaphyseal dysplasia with joint laxity, type 1, this association is not yet strongly established based on the criteria laid out in Tayoun, 2018 (PMID: 30192042). In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PVS1_Supporting, PM3 (Richards 2015). -

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

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 25, 2024

This sequence change results in a frameshift in the B3GALT6 gene (p.Arg197Alafs*246). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 133 amino acid(s) of the B3GALT6 protein and extend the protein by 112 additional amino acid residues. 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 frameshift has been observed in individual(s) with clinical features of B3GALT6-related conditions (PMID: 34529350). ClinVar contains an entry for this variant (Variation ID: 427130). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. This variant results in an extension of the B3GALT6 protein. Other variant(s) that result in a similarly extended protein product (p.Ile328Hisfs*115) have been observed in individuals with B3GALT6-related disease (Invitae). This suggests that these extensions may be clinically significant. 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

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