NM_080605.4:c.588dupG

Variant names:

• chr1-1232859-C-CG
• rs533071750
• NM_080605.4:c.588dupG

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PVS1_Strong PP5

The NM_080605.4(B3GALT6):​c.588dupG​(p.Arg197AlafsTer246) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000145 in 1,533,176 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. R197R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00014 (0 hom.)
• Consequence: B3GALT6 NM_080605.4 frameshift
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:3
• Conservation: PhyloP100: -8.47
• Publications: 6 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: Uncertain_significance. The variant received 5 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 16 pathogenic variants in the truncated region.
• PP5: Variant 1-1232859-C-CG is Pathogenic according to our data. Variant chr1-1232859-C-CG is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 427130.

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.588dupG	p.Arg197AlafsTer246	frameshift	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.588dupG	p.Arg197AlafsTer246	frameshift	Exon 1 of 1	ENSP00000368496.2	Q96L58
	SDF4	ENST00000900948.1		c.-174-3914dupC		intron	N/A	ENSP00000571007.1

Frequencies

GnomAD3 genomes AF: 0.000158 AC: 24 AN: 151792 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000968

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.000958

GnomAD2 exomes AF: 0.000222 AC: 31 AN: 139924 AF XY: 0.000237

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000457

Gnomad ASJ exome AF: 0.000150

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000229

Gnomad OTH exome AF: 0.000275

GnomAD4 exome AF: 0.000143 AC: 198 AN: 1381276 Hom.: 0 Cov.: 31 AF XY: 0.000142 AC XY: 97 AN XY: 684756

African (AFR) AF: 0.000104 AC: 3 AN: 28736

American (AMR) AF: 0.000409 AC: 14 AN: 34202

Ashkenazi Jewish (ASJ) AF: 0.0000419 AC: 1 AN: 23872

East Asian (EAS) AF: 0.000145 AC: 5 AN: 34524

South Asian (SAS) AF: 0.000182 AC: 14 AN: 77094

European-Finnish (FIN) AF: 0.0000285 AC: 1 AN: 35124

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4134

European-Non Finnish (NFE) AF: 0.000141 AC: 153 AN: 1086270

Other (OTH) AF: 0.000122 AC: 7 AN: 57320

GnomAD4 genome AF: 0.000158 AC: 24 AN: 151900 Hom.: 0 Cov.: 33 AF XY: 0.000148 AC XY: 11 AN XY: 74248

African (AFR) AF: 0.0000965 AC: 4 AN: 41454

American (AMR) AF: 0.000131 AC: 2 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000387 AC: 2 AN: 5162

South Asian (SAS) AF: 0.00 AC: 0 AN: 4810

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10544

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.000206 AC: 14 AN: 67884

Other (OTH) AF: 0.000948 AC: 2 AN: 2110

Alfa AF: 0.000349 Hom.: 0

Bravo AF: 0.000155

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
1	1	-	not provided (2)
1	-	-	Al-Gazali syndrome (1)
-	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
PhyloP100		-8.5
Mutation Taster		=61/139	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: rs533071750; hg19: chr1-1168239; COSMIC: COSV55419011; COSMIC: COSV55419011;