chr1-1232471-A-G

Variant names:

• chr1-1232471-A-G
• rs397514719
• NM_080605.4:c.193A>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 4P and 1B. PM2 PP2 PP5 BP4

The NM_080605.4(B3GALT6):​c.193A>G​(p.Ser65Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000346 in 866,258 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S65C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000035 (0 hom.)
• Consequence: B3GALT6 NM_080605.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 2.09
• Publications: 9 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: Uncertain_significance. The variant received 3 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.
• PP5: Variant 1-1232471-A-G is Pathogenic according to our data. Variant chr1-1232471-A-G is described in ClinVar as Pathogenic. ClinVar VariationId is 60488.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.42055872). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
B3GALT6	NM_080605.4	c.193A>G	p.Ser65Gly	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.193A>G	p.Ser65Gly	missense_variant	Exon 1 of 1	6	NM_080605.4	ENSP00000368496.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000346 AC: 3 AN: 866258 Hom.: 0 Cov.: 30 AF XY: 0.00000248 AC XY: 1 AN XY: 403256

African (AFR) AF: 0.00 AC: 0 AN: 16432

American (AMR) AF: 0.00 AC: 0 AN: 2162

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 5960

East Asian (EAS) AF: 0.00 AC: 0 AN: 4834

South Asian (SAS) AF: 0.00 AC: 0 AN: 17612

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 4108

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1774

European-Non Finnish (NFE) AF: 0.00000383 AC: 3 AN: 784076

Other (OTH) AF: 0.00 AC: 0 AN: 29300

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

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.45
BayesDel_addAF	Benign	-0.0055	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	21
DANN	Benign	0.94
DEOGEN2	Benign	0.41	T;T
Eigen	Benign	-0.14
Eigen_PC	Benign	-0.081
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.44	.;T
M_CAP	Pathogenic	0.94	D
MetaRNN	Benign	0.42	T;T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	1.6	L;L
PhyloP100		2.1
PrimateAI	Pathogenic	0.93	D
PROVEAN	Uncertain	-3.3	.;D
REVEL	Benign	0.21
Sift	Uncertain	0.0030	.;D
Sift4G	Uncertain	0.0050	.;D
Polyphen		0.46	P;P
Vest4		0.69
MutPred		0.34		Loss of glycosylation at S65 (P = 0.0118);Loss of glycosylation at S65 (P = 0.0118);
MVP		0.71
MPC		1.0
ClinPred		0.90	D
GERP RS		3.5
PromoterAI		0.032	Neutral
Varity_R		0.77
gMVP		0.82
Mutation Taster		=14/86	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs397514719; hg19: chr1-1167851;