chr1-1232295-G-A

Variant names:

• chr1-1232295-G-A
• rs1131691530
• NM_080605.4:c.17G>A

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 1P and 7B. PP2 BP4_Moderate BS1_Supporting BS2

The NM_080605.4(B3GALT6):​c.17G>A​(p.Arg6Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000722 in 981,976 control chromosomes in the GnomAD database, including 2 homozygotes. 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R6W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00040 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00078 (2 hom.)
• Consequence: B3GALT6 NM_080605.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:8 O:1
• Conservation: PhyloP100: 0.616
• Publications: 0 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_benign. The variant received -6 ACMG points.

• 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.15255421).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000397 (58/146176) while in subpopulation NFE AF = 0.00076 (50/65780). AF 95% confidence interval is 0.000592. There are 0 homozygotes in GnomAd4. There are 28 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

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.17G>A	p.Arg6Gln	missense	Exon 1 of 1	NP_542172.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	B3GALT6	ENST00000379198.5	TSL:6 MANE Select	c.17G>A	p.Arg6Gln	missense	Exon 1 of 1	ENSP00000368496.2
	SDF4	ENST00000900948.1		c.-174-3349C>T		intron	N/A	ENSP00000571007.1
	SDF4	ENST00000900949.1		c.-963C>T		upstream_gene	N/A	ENSP00000571008.1

Frequencies

GnomAD3 genomes AF: 0.000397 AC: 58 AN: 146176 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000147

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000680

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000120

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000760

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000779 AC: 651 AN: 835800 Hom.: 2 Cov.: 29 AF XY: 0.000829 AC XY: 320 AN XY: 386226

African (AFR) AF: 0.0000633 AC: 1 AN: 15810

American (AMR) AF: 0.00 AC: 0 AN: 1060

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 5198

East Asian (EAS) AF: 0.00 AC: 0 AN: 3668

South Asian (SAS) AF: 0.00 AC: 0 AN: 17282

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 406

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1630

European-Non Finnish (NFE) AF: 0.000836 AC: 638 AN: 763334

Other (OTH) AF: 0.000438 AC: 12 AN: 27412

GnomAD4 genome AF: 0.000397 AC: 58 AN: 146176 Hom.: 0 Cov.: 33 AF XY: 0.000394 AC XY: 28 AN XY: 71116

African (AFR) AF: 0.000147 AC: 6 AN: 40812

American (AMR) AF: 0.0000680 AC: 1 AN: 14714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3394

East Asian (EAS) AF: 0.00 AC: 0 AN: 5082

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.000120 AC: 1 AN: 8342

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 306

European-Non Finnish (NFE) AF: 0.000760 AC: 50 AN: 65780

Other (OTH) AF: 0.00 AC: 0 AN: 2018

Alfa AF: 0.000216 Hom.: 1

Bravo AF: 0.000400

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	4	-	not provided (5)
-	1	-	Al-Gazali syndrome;C3809210:Ehlers-Danlos syndrome, spondylodysplastic type, 2;C4017377:Spondyloepimetaphyseal dysplasia with joint laxity, type 1, with or without fractures (1)
-	1	-	Inborn genetic diseases (1)
-	1	-	not specified (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	Benign	0.16
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0093	T
Eigen	Benign	-0.41
Eigen_PC	Benign	-0.43
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.61	T
M_CAP	Pathogenic	0.55	D
MetaRNN	Benign	0.15	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.5	L
PhyloP100		0.62
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-0.92	N
REVEL	Benign	0.058
Sift	Benign	0.097	T
Sift4G	Benign	0.11	T
Polyphen		0.95	P
Vest4		0.061
MVP		0.61
MPC		1.1
ClinPred		0.32	T
GERP RS		2.5
PromoterAI		-0.0073	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.0
Varity_R		0.14
gMVP		0.48
Mutation Taster		=89/11	polymorphism

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: rs1131691530; hg19: chr1-1167675;