rs786200938

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr1-1232279-A-C
• chr1-1232279-A-G
• chr1-1232279-A-T

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PS1_Moderate PS3 PM2 PP5_Moderate

The NM_080605.4(B3GALT6):​c.1A>C​(p.Met1?) variant causes a initiator codon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000048 in 834,202 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 Pathogenic (★). ClinVar reports functional evidence for this variant: "SCV005068324: Functional study demonstrated the mutant B3GALT6 protein with c.1A>G had a molecular weight ~4 kD lower compared with the wildtype protein, suggesting the mutation in the initiation codon probably resulted in an N-terminal deletion of 41 amino acids (PMID:23664117).".

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: B3GALT6 NM_080605.4 initiator_codon
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• 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 18 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: SCV005068324: Functional study demonstrated the mutant B3GALT6 protein with c.1A>G had a molecular weight ~4 kD lower compared with the wildtype protein, suggesting the mutation in the initiation codon probably resulted in an N-terminal deletion of 41 amino acids (PMID: 23664117).
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-1232279-A-C is Pathogenic according to our data. Variant chr1-1232279-A-C is described in ClinVar as Pathogenic. ClinVar VariationId is 3250476.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.1A>C	p.Met1?	initiator_codon	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>C	p.Met1?	initiator_codon	Exon 1 of 1	ENSP00000368496.2	Q96L58
	SDF4	ENST00000900948.1		c.-174-3333T>G		intron	N/A	ENSP00000571007.1
	SDF4	ENST00000263741.12	TSL:1	c.-562T>G		upstream_gene	N/A	ENSP00000263741.8	A0A5F9UJX7

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000479 AC: 4 AN: 834202 Hom.: 0 Cov.: 29 AF XY: 0.00000259 AC XY: 1 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: 0.00 AC: 0 AN: 17260

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

Middle Eastern (MID) AF: 0.000614 AC: 1 AN: 1628

European-Non Finnish (NFE) AF: 0.00000393 AC: 3 AN: 762742

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

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Al-Gazali syndrome;C3809210:Ehlers-Danlos syndrome, spondylodysplastic type, 2;C4017377:Spondyloepimetaphyseal dysplasia with joint laxity, type 1, with or without fractures (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.057	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	20
DANN	Benign	0.66
DEOGEN2	Benign	0.0027	T
Eigen	Benign	-0.50
Eigen_PC	Benign	-0.48
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.96	D
MetaRNN	Pathogenic	0.80	D
MetaSVM	Benign	-1.1	T
PhyloP100		2.0
PROVEAN	Benign	-0.62	N
REVEL	Benign	0.23
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.0	B
Vest4		0.71
MutPred		0.85		Loss of catalytic residue at M1 (P = 0.1551)
MVP		0.56
ClinPred		0.98	D
GERP RS		2.6
PromoterAI		-0.27	Neutral
Varity_R		0.95
gMVP		0.57
Mutation Taster		=42/158	disease causing

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;