1-1233177-G-C

Variant names:

• chr1-1233177-G-C
• rs786200939
• NM_080605.4:c.899G>C

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM2 PP2 PP3_Strong PP5

The NM_080605.4(B3GALT6):​c.899G>C​(p.Cys300Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: B3GALT6 NM_080605.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 5.54
• Publications: 7 publications found

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

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.976
• PP5: Variant 1-1233177-G-C is Pathogenic according to our data. Variant chr1-1233177-G-C is described in ClinVar as Pathogenic. ClinVar VariationId is 60487.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
B3GALT6	NM_080605.4	c.899G>C	p.Cys300Ser	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	c.899G>C	p.Cys300Ser	missense_variant	Exon 1 of 1	6	NM_080605.4	ENSP00000368496.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

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

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.22
CADD	Pathogenic	29
DANN	Uncertain	0.99
DEOGEN2	Benign	0.38	T;T
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.0	.;D
M_CAP	Pathogenic	0.68	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Uncertain	-0.16	T
MutationAssessor	Uncertain	2.9	M;M
PhyloP100		5.5
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	0.0	.;D
REVEL	Benign	0.0
Sift	Pathogenic	0.0	.;D
Sift4G	Pathogenic	0.0	.;D
Vest4		0.0
ClinPred		1.0	D
GERP RS		4.3
Varity_R		0.96
gMVP		0.97
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs786200939; hg19: chr1-1168557;