rs397514724

Variant names:

• chr1-1232927-G-A
• rs397514724
• NM_080605.4:c.649G>A

Your query was ambiguous. Multiple possible variants found:

• chr1-1232927-G-A
• chr1-1232927-G-T

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.649G>A​(p.Gly217Ser) 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). Synonymous variant affecting the same amino acid position (i.e. G217G) 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: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 6.66
• Publications: 8 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 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, 0.98
• PP5: Variant 1-1232927-G-A is Pathogenic according to our data. Variant chr1-1232927-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 60496.Status of the report is no_assertion_criteria_provided, 0 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.649G>A	p.Gly217Ser	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.649G>A	p.Gly217Ser	missense	Exon 1 of 1	ENSP00000368496.2	Q96L58
	SDF4	ENST00000900948.1		c.-174-3981C>T		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: 1412724 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 700508

African (AFR) AF: 0.00 AC: 0 AN: 31956

American (AMR) AF: 0.00 AC: 0 AN: 40686

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25316

East Asian (EAS) AF: 0.00 AC: 0 AN: 37462

South Asian (SAS) AF: 0.00 AC: 0 AN: 81818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 36346

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4356

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1096194

Other (OTH) AF: 0.00 AC: 0 AN: 58590

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Spondyloepimetaphyseal dysplasia with joint laxity, type 1, with fractures (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Benign	0.25	T
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.95	D
M_CAP	Pathogenic	0.96	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Uncertain	0.050	D
MutationAssessor	Pathogenic	4.1	H
PhyloP100		6.7
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-6.0	D
REVEL	Uncertain	0.63
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.84
MutPred		0.92		Loss of helix (P = 0.1299)
MVP		0.84
MPC		2.1
ClinPred		1.0	D
GERP RS		3.9
Varity_R		0.98
gMVP		0.88
Mutation Taster		=4/96	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: rs397514724; hg19: chr1-1168307; COSMIC: COSV55420366; COSMIC: COSV55420366;