rs28937869

Variant names:

• chr5-177608994-C-T
• rs28937869
• NM_007255.3:c.808C>T

Your query was ambiguous. Multiple possible variants found:

• chr5-177608994-C-T
• chr5-177608994-C-A

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PS3 PP3_Strong PP5_Very_Strong

The NM_007255.3(B4GALT7):​c.808C>T​(p.Arg270Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000134 in 1,612,206 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: "SCV000490422: Published functional studies showed reduction of galactosyltransferase activity which results in reduction of glycosaminoglycans synthesis (Bui et al., 2010" and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R270H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000079 (0 hom., cov: 34)
  • Exomes 𝑓: 0.00014 (0 hom.)
• Consequence: B4GALT7 NM_007255.3 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 2.06
• Publications: 25 publications found

Genes affected

B4GALT7 (HGNC:930): (beta-1,4-galactosyltransferase 7) This gene is a member of the beta-1,4-galactosyltransferase (beta4GalT) family. Family members encode type II membrane-bound glycoproteins that appear to have exclusive specificity for the donor substrate UDP-galactose. Each beta4GalT member has a distinct function in the biosynthesis of different glycoconjugates and saccharide structures. As type II membrane proteins, they have an N-terminal hydrophobic signal sequence that directs the protein to the Golgi apparatus which then remains uncleaved to function as a transmembrane anchor. The enzyme encoded by this gene attaches the first galactose in the common carbohydrate-protein linkage (GlcA-beta1,3-Gal-beta1,3-Gal-beta1,4-Xyl-beta1-O-Ser) found in proteoglycans. This enzyme differs from other beta4GalTs because it lacks the conserved Cys residues found in beta4GalT1-beta4GalT6 and it is located in cis-Golgi instead of trans-Golgi. Mutations in this gene have been associated with the progeroid form of Ehlers-Danlos syndrome. [provided by RefSeq, Oct 2009]

B4GALT7 Gene-Disease associations (from GenCC):

• Ehlers-Danlos syndrome, spondylodysplastic type, 1

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen
• Ehlers-Danlos syndrome, spondylodysplastic type

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000490422: Published functional studies showed reduction of galactosyltransferase activity which results in reduction of glycosaminoglycans synthesis (Bui et al., 2010; Rahuel-Clermont et al., 2010; Mihalic Mosher et al., 2019); SCV000914237: In vitro enzyme assays confirmed a reduced level of enzyme activity for this variant.; SCV002162238: Experimental studies have shown that this missense change affects B4GALT7 function (PMID: 20691685, 20809901, 31278392).
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.954
• PP5: Variant 5-177608994-C-T is Pathogenic according to our data. Variant chr5-177608994-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 5613.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_007255.3. 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
	B4GALT7	NM_007255.3	MANE Select	c.808C>T	p.Arg270Cys	missense	Exon 5 of 6	NP_009186.1	Q9UBV7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	B4GALT7	ENST00000029410.10	TSL:1 MANE Select	c.808C>T	p.Arg270Cys	missense	Exon 5 of 6	ENSP00000029410.5	Q9UBV7
	B4GALT7	ENST00000871348.1		c.970C>T	p.Arg324Cys	missense	Exon 6 of 7	ENSP00000541407.1
	B4GALT7	ENST00000966184.1		c.853C>T	p.Arg285Cys	missense	Exon 5 of 6	ENSP00000636243.1

Frequencies

GnomAD3 genomes AF: 0.0000854 AC: 13 AN: 152224 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

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: 0.000176

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000482 AC: 12 AN: 249168 AF XY: 0.0000371

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000545

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000969

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000140 AC: 204 AN: 1459864 Hom.: 0 Cov.: 36 AF XY: 0.000123 AC XY: 89 AN XY: 726380

African (AFR) AF: 0.0000299 AC: 1 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51560

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5766

European-Non Finnish (NFE) AF: 0.000174 AC: 194 AN: 1111882

Other (OTH) AF: 0.000116 AC: 7 AN: 60374

GnomAD4 genome AF: 0.0000788 AC: 12 AN: 152342 Hom.: 0 Cov.: 34 AF XY: 0.000107 AC XY: 8 AN XY: 74494

African (AFR) AF: 0.00 AC: 0 AN: 41580

American (AMR) AF: 0.00 AC: 0 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000176 AC: 12 AN: 68036

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.0000956 Hom.: 0

Bravo AF: 0.0000567

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.0000659 AC: 8

EpiCase AF: 0.000164

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	Ehlers-Danlos syndrome progeroid type (2)
2	-	-	not provided (2)
1	-	-	Ehlers-Danlos syndrome, spondylodysplastic type, 1 (1)
1	-	-	Larsen-like syndrome, B3GAT3 type (1)
1	-	-	Lethal skeletal dysplasia (1)
1	-	-	Not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Uncertain	0.13
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.38	T
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Uncertain	0.097	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Benign	-0.36	T
MutationAssessor	Uncertain	2.7	M
PhyloP100		2.1
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-4.7	D
REVEL	Uncertain	0.47
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.019	D
Polyphen		1.0	D
Vest4		0.93
MutPred		0.83		Loss of MoRF binding (P = 0.0051)
MVP		0.64
MPC		0.75
ClinPred		0.88	D
GERP RS		5.5
Varity_R		0.51
gMVP		0.80
Mutation Taster		=26/74	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: rs28937869; hg19: chr5-177035995; COSMIC: COSV99219107; COSMIC: COSV99219107;