rs969701761

Variant names:

• chr1-1232280-T-A
• rs969701761
• NM_080605.4:c.2T>A

Your query was ambiguous. Multiple possible variants found:

• chr1-1232280-T-A
• chr1-1232280-T-C
• chr1-1232280-T-G

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PVS1 PS1_Moderate PM2 PP5_Moderate

The NM_080605.4(B3GALT6):​c.2T>A​(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 0.00000694 in 144,108 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 (★).

• Frequency: Genomes: 𝑓 0.0000069 (0 hom., cov: 32)
• Consequence: B3GALT6 NM_080605.4 start_lost
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 1.18
• 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: Pathogenic. The variant received 14 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
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-1232280-T-A is Pathogenic according to our data. Variant chr1-1232280-T-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 1067539.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.2T>A	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.2T>A	p.Met1?	start_lost	Exon 1 of 1	ENSP00000368496.2	Q96L58
	SDF4	ENST00000900948.1		c.-174-3334A>T		intron	N/A	ENSP00000571007.1
	SDF4	ENST00000263741.12	TSL:1	c.-563A>T		upstream_gene	N/A	ENSP00000263741.8	A0A5F9UJX7

Frequencies

GnomAD3 genomes AF: 0.00000694 AC: 1 AN: 144108 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000209

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 29

GnomAD4 genome AF: 0.00000694 AC: 1 AN: 144108 Hom.: 0 Cov.: 32 AF XY: 0.0000143 AC XY: 1 AN XY: 70136

African (AFR) AF: 0.00 AC: 0 AN: 39474

American (AMR) AF: 0.00 AC: 0 AN: 14632

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3372

East Asian (EAS) AF: 0.00 AC: 0 AN: 4944

South Asian (SAS) AF: 0.000209 AC: 1 AN: 4782

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8248

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 304

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 65472

Other (OTH) AF: 0.00 AC: 0 AN: 1976

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
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	Pathogenic	0.62	D
BayesDel_noAF	Benign	-0.090
CADD	Benign	22
DANN	Benign	0.93
DEOGEN2	Benign	0.0078	T
Eigen	Benign	-0.46
Eigen_PC	Benign	-0.46
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.98	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Benign	-1.0	T
PhyloP100		1.2
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.21
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.24	B
Vest4		0.75
MutPred		0.86		Gain of solvent accessibility (P = 0.0063)
MVP		0.53
ClinPred		0.99	D
GERP RS		2.4
PromoterAI		-0.30	Neutral
Varity_R		0.96
gMVP		0.89
Mutation Taster		=28/172	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: rs969701761; hg19: chr1-1167660;