1-1232897-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PP3_Moderate PP5_Moderate

The NM_080605.4(B3GALT6):c.619G>C(p.Asp207His) variant causes a missense change. The variant allele was found at a frequency of 0.000000709 in 1,410,110 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D207E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: B3GALT6 NM_080605.4 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 6.69

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_pathogenic. Variant got 8 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_080605.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.899
• PP5: Variant 1-1232897-G-C is Pathogenic according to our data. Variant chr1-1232897-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 60495.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	c.619G>C	p.Asp207His	missense_variant	1/1	ENST00000379198.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
B3GALT6	ENST00000379198.5	c.619G>C	p.Asp207His	missense_variant	1/1		NM_080605.4	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.09e-7 AC: 1 AN: 1410110 Hom.: 0 Cov.: 31 AF XY: 0.00000143 AC XY: 1 AN XY: 700376

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: 0.0000123

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Spondyloepimetaphyseal dysplasia with joint laxity, type 1, with fractures Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jun 06, 2013

- -

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

Pathogenic, criteria provided, single submitter

clinical testing

Payam Genetics Center, General Welfare Department of North Khorasan Province

Mar 01, 2023

The B3GALT6 c.619G>C (p.D207H) is a missense mutation and results at the protein level is a dysfunctional that predicted lead to disease. This variant is not present in Iranian population databases. This variant as Pathogenic according to the AMCG classification. A 11 years old boy suffering from autosomal recessive Spondyloepimetaphyseal dysplasia with joint laxity type1 with fractures Ehlers-Donlos syndrome, Spondylodysplastic type2 is homozygous that the parents are not related, is Heterozygous. This mutation has been reported for its pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Uncertain	0.029	T
BayesDel_noAF	Benign	-0.20
Cadd	Pathogenic	32
Dann	Uncertain	0.99
DEOGEN2	Benign	0.14	T;T
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Uncertain	0.96	D
M_CAP	Pathogenic	0.96	D
MetaRNN	Pathogenic	0.90	D;D
MetaSVM	Benign	-0.42	T
MutationAssessor	Pathogenic	2.9	M;M
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.91	D
Polyphen		1.0	D;D
Vest4		0.86
MutPred		0.62		Gain of MoRF binding (P = 0.055);Gain of MoRF binding (P = 0.055);
MVP		0.79
MPC		2.2
ClinPred		1.0	D
GERP RS		3.9
Varity_R		0.97
gMVP		0.88

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

Other links and lift over

dbSNP: rs397514723; hg19: chr1-1168277;