1-1232279-A-G

Variant names:

• chr1-1232279-A-G
• rs786200938
• NM_080605.4:c.1A>G

Variant summary

Our verdict is Pathogenic. The variant received 24 ACMG points: 24P and 0B. PVS1 PS1_Moderate PS3 PM2 PP5_Very_Strong

The NM_080605.4(B3GALT6):​c.1A>G​(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000164 in 978,580 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV001782523: Published functional studies demonstrate a damaging effect as this variant results in a reduced molecular weight and mislocalization of the mutant protein compared to wild type, suggesting the c.1 A>G variant results in the use of an alternate initiation codon at c.124, causing an N-terminal deletion of 41 amino acids (Nakajima et al., 2013)" and additional evidence is available in ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000048 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: B3GALT6 NM_080605.4 start_lost
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 2.03
• 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]

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: Pathogenic. The variant received 24 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 7 pathogenic variants. Next in-frame start position is after 42 codons. Genomic position: 1232402. Lost 0.125 part of the original CDS.
• PS1: Another start lost variant in NM_080605.4 (B3GALT6) was described as [Likely_pathogenic] in ClinVar
• PS3: PS3 evidence extracted from ClinVar submissions: SCV001782523: Published functional studies demonstrate a damaging effect as this variant results in a reduced molecular weight and mislocalization of the mutant protein compared to wild type, suggesting the c.1 A>G variant results in the use of an alternate initiation codon at c.124, causing an N-terminal deletion of 41 amino acids (Nakajima et al., 2013); SCV002117895: Experimental studies have shown that disruption of the initiator codon affects B3GALT6 function (PMID: 23664117).; SCV004763794: "In vitro functional studies found that this variant yields a shorter protein compared to the wild type form; and, is localized in the cytoplasm and nucleus while the wild type is found in the Golgi apparatus." PMID:23664117
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-1232279-A-G is Pathogenic according to our data. Variant chr1-1232279-A-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 60484.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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.1A>G	p.Met1?	start_lost	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.1A>G	p.Met1?	start_lost	Exon 1 of 1	ENSP00000368496.2	Q96L58
	SDF4	ENST00000900948.1		c.-174-3333T>C		intron	N/A	ENSP00000571007.1
	SDF4	ENST00000263741.12	TSL:1	c.-562T>C		upstream_gene	N/A	ENSP00000263741.8	A0A5F9UJX7

Frequencies

GnomAD3 genomes AF: 0.0000416 AC: 6 AN: 144262 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000253

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000683

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000611

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000108 AC: 9 AN: 834202 Hom.: 0 Cov.: 29 AF XY: 0.00000778 AC XY: 3 AN XY: 385392

African (AFR) AF: 0.00 AC: 0 AN: 15094

American (AMR) AF: 0.00 AC: 0 AN: 1038

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 5130

East Asian (EAS) AF: 0.00 AC: 0 AN: 3648

South Asian (SAS) AF: 0.000116 AC: 2 AN: 17260

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 358

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1628

European-Non Finnish (NFE) AF: 0.00000918 AC: 7 AN: 762742

Other (OTH) AF: 0.00 AC: 0 AN: 27304

GnomAD4 genome AF: 0.0000485 AC: 7 AN: 144378 Hom.: 0 Cov.: 33 AF XY: 0.0000427 AC XY: 3 AN XY: 70306

African (AFR) AF: 0.0000504 AC: 2 AN: 39680

American (AMR) AF: 0.0000682 AC: 1 AN: 14658

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3376

East Asian (EAS) AF: 0.00 AC: 0 AN: 4954

South Asian (SAS) AF: 0.00 AC: 0 AN: 4770

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8270

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 280

European-Non Finnish (NFE) AF: 0.0000611 AC: 4 AN: 65482

Other (OTH) AF: 0.00 AC: 0 AN: 2006

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000416

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
1	-	-	B3GALT6-related disorder (1)
1	-	-	Ehlers-Danlos syndrome, spondylodysplastic type, 2 (1)
1	-	-	not provided (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
BayesDel_addAF	Uncertain	0.034	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	20
DANN	Benign	0.72
DEOGEN2	Benign	0.0072	T
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.46
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.97	D
MetaRNN	Pathogenic	0.87	D
MetaSVM	Benign	-1.1	T
PhyloP100		2.0
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.19
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.063	B
Vest4		0.77
MutPred		0.89		Gain of relative solvent accessibility (P = 0.0166)
MVP		0.61
ClinPred		0.97	D
GERP RS		2.6
PromoterAI		-0.27	Neutral
Varity_R		0.94
gMVP		0.71
Mutation Taster		=42/158	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: rs786200938; hg19: chr1-1167659;