1-1232288-C-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_080605.4(B3GALT6):c.10C>G(p.Leu4Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. L4L) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: B3GALT6 NM_080605.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.101

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]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.057198167).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
B3GALT6	NM_080605.4	c.10C>G	p.Leu4Val	missense_variant	1/1	ENST00000379198.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
B3GALT6	ENST00000379198.5	c.10C>G	p.Leu4Val	missense_variant	1/1		NM_080605.4	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 835518 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 386050

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Spondyloepimetaphyseal dysplasia with joint laxity;C3809210:Ehlers-Danlos syndrome, spondylodysplastic type, 2 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Mar 12, 2022

The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the gnomAD database. 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. 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"). This variant has not been reported in the literature in individuals affected with B3GALT6-related conditions. This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 4 of the B3GALT6 protein (p.Leu4Val). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.095
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.70
Cadd	Benign	14
Dann	Benign	0.70
DEOGEN2	Benign	0.0047	T;T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.72	D
M_CAP	Uncertain	0.27	D
MetaRNN	Benign	0.057	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.90	L;L
MutationTaster	Benign	1.0	N
PrimateAI	Pathogenic	0.83	D
Polyphen		0.0030	B;B
Vest4		0.035
MutPred		0.31		Loss of helix (P = 0.0196);Loss of helix (P = 0.0196);
MVP		0.47
MPC		0.93
ClinPred		0.082	T
GERP RS		1.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.049
gMVP		0.29

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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

Other links and lift over

dbSNP: rs928368471; hg19: chr1-1167668;