rs397514720

Variant names:

• chr1-1232478-C-T
• rs397514720
• NM_080605.4:c.200C>T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP2 PP3 PP5_Moderate

The NM_080605.4(B3GALT6):​c.200C>T​(p.Pro67Leu) 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 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. P67T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: B3GALT6 NM_080605.4 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 2.03
• 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]

SDF4 (HGNC:24188): (stromal cell derived factor 4) This gene encodes a stromal cell derived factor that is a member of the CREC protein family. The encoded protein contains six EF-hand motifs and calcium-binding motifs. This protein localizes to the Golgi lumen and may be involved in regulating calcium dependent cellular activities. [provided by RefSeq, Sep 2011]

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 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, 0.769
• PP5: Variant 1-1232478-C-T is Pathogenic according to our data. Variant chr1-1232478-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 60489.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_080605.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	B3GALT6	NM_080605.4	MANE Select	c.200C>T	p.Pro67Leu	missense	Exon 1 of 1	NP_542172.2	Q96L58

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	B3GALT6	ENST00000379198.5	TSL:6 MANE Select	c.200C>T	p.Pro67Leu	missense	Exon 1 of 1	ENSP00000368496.2	Q96L58
	SDF4	ENST00000900948.1		c.-174-3532G>A		intron	N/A	ENSP00000571007.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 876386 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 408524

African (AFR) AF: 0.00 AC: 0 AN: 16660

American (AMR) AF: 0.00 AC: 0 AN: 2482

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 6288

East Asian (EAS) AF: 0.00 AC: 0 AN: 5452

South Asian (SAS) AF: 0.00 AC: 0 AN: 17716

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5218

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1832

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 790806

Other (OTH) AF: 0.00 AC: 0 AN: 29932

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Spondyloepimetaphyseal dysplasia with joint laxity, type 1, with or without fractures (1)
1	-	-	Spondyloepimetaphyseal dysplasia with joint laxity;C3809210:Ehlers-Danlos syndrome, spondylodysplastic type, 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Benign	0.0050	T
BayesDel_noAF	Benign	-0.23
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.12	T
Eigen	Uncertain	0.30
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.64	T
M_CAP	Pathogenic	0.98	D
MetaRNN	Pathogenic	0.77	D
MetaSVM	Benign	-0.62	T
MutationAssessor	Benign	1.8	L
PhyloP100		2.0
PrimateAI	Pathogenic	0.93	D
PROVEAN	Pathogenic	-7.6	D
REVEL	Benign	0.29
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.022	D
Polyphen		1.0	D
Vest4		0.68
MutPred		0.37		Loss of loop (P = 9e-04)
MVP		0.82
MPC		1.8
ClinPred		1.0	D
GERP RS		3.6
PromoterAI		0.035	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.73
gMVP		0.80
Mutation Taster		=10/90	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: rs397514720; hg19: chr1-1167858;