rs28937869

Positions:

chr5-177608994-C-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_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 (★★).

Frequency

Genomes: 𝑓 0.000079 ( 0 hom., cov: 34)

Exomes 𝑓: 0.00014 ( 0 hom. )

Consequence

B4GALT7
NM_007255.3 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:8

Conservation

PhyloP100: 2.06

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

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 id is 5613.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-177608994-C-T is described in Lovd as [Pathogenic]. Variant chr5-177608994-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
B4GALT7	NM_007255.3 linkuse as main transcript	c.808C>T	p.Arg270Cys	missense_variant	5/6	ENST00000029410.10	NP_009186.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
B4GALT7	ENST00000029410.10 linkuse as main transcript	c.808C>T	p.Arg270Cys	missense_variant	5/6	1	NM_007255.3	ENSP00000029410	P1
B4GALT7	ENST00000505145.1 linkuse as main transcript	n.1906C>T		non_coding_transcript_exon_variant	3/4	2
B4GALT7	ENST00000515353.1 linkuse as main transcript	n.1630C>T		non_coding_transcript_exon_variant	1/2	2
B4GALT7	ENST00000505433.5 linkuse as main transcript	c.*314C>T		3_prime_UTR_variant, NMD_transcript_variant	5/6	5		ENSP00000425591

Frequencies

GnomAD3 genomes

AF:

0.0000854

AC:

AN:

152224

Hom.:

Cov.:

show subpopulations

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

GnomAD3 exomes

AF:

0.0000482

AC:

AN:

249168

Hom.:

AF XY:

0.0000371

AC XY:

AN XY:

134924

show subpopulations

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 SAS exome

AF:

0.00

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.:

Cov.:

AF XY:

0.000123

AC XY:

AN XY:

726380

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000174

Gnomad4 OTH exome

AF:

0.000116

GnomAD4 genome

AF:

0.0000788

AC:

AN:

152342

Hom.:

Cov.:

AF XY:

0.000107

AC XY:

AN XY:

74494

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000176

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000672

Hom.:

Bravo

AF:

0.0000567

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ExAC

AF:

0.0000659

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Ehlers-Danlos syndrome progeroid type

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	Aug 01, 2020	A homozygous missense variation in exon 5 of the B4GALT7 gene that results in the amino acid substitution of Cysteine for Arginine at codon 270 was detected. The variant previously been detected in patients affected with Ehlers-Danlos syndrome (Jaenken et al 2017). The variant c.808C>T (p.Arg270Cys) has not been reported in the 1000 genomes database and has a minor allele frequency of 0.005% in the gnomAD database. The in silico prediction of the variant are possibly damaging by PolyPhen-2 (HumDiv) and damaging by SIFT, LRT and MutationTaster2. The reference codon is conserved across species. The observed variation has previously been reported in patients affected with Ehlers-Danlos Syndrome and is one of the most prevalent variants. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 08, 2023	Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on B4GALT7 protein function. This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 270 of the B4GALT7 protein (p.Arg270Cys). This variant is present in population databases (rs28937869, gnomAD 0.01%). This missense change has been observed in individuals with B4GALT7-related conditions (PMID: 15211654, 24755949, 25533962, 31278392). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 5613). Experimental studies have shown that this missense change affects B4GALT7 function (PMID: 20691685, 20809901, 31278392). For these reasons, this variant has been classified as Pathogenic. -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 22, 2022	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); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 28346368, 28882145, 24970356, 30914273, 20809901, 15211654, 20691685, 23956117, 25533962, 24755949, 26940150, 28306225, 28229453, 31614862, 31862401, 31278392, 18158310, 31589614) -

Larsen-like syndrome, B3GAT3 type

Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center

Nov 01, 2016

Clinical exome sequencing revealed NM_007255.1:c.808C>T:p.R270C (NC_000005.9:g.177035995C>T), the same published variant (PMID: 24755949) that causes autosomal recessive Larsen syndrome, so we believe this is a likely pathogenic variant. -

Lethal skeletal dysplasia

Pathogenic:1

Pathogenic, criteria provided, single submitter

research

Institute for Genomic Medicine, Nationwide Children's Hospital

May 23, 2019

This variant has been observed in 13 out of 122,110 gnomAD individuals (13 heterozygotes, MAF=0.00005323), making it extremely rare. It is a known pathogenic variant previously associated with Larsen syndrome of Reunion Island, and is predicted to be damaging by a majority of in silico tools. In vitro enzyme assays confirmed a reduced level of enzyme activity for this variant. -

Ehlers-Danlos syndrome, spondylodysplastic type, 1

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 28, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.90

BayesDel_addAF

Uncertain

0.10

BayesDel_noAF

Uncertain

0.13

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.38

Eigen

Uncertain

0.60

Eigen_PC

Uncertain

0.54

FATHMM_MKL

Uncertain

0.90

LIST_S2

Pathogenic

0.98

M_CAP

Uncertain

0.097

MetaRNN

Pathogenic

0.95

MetaSVM

Benign

-0.36

MutationAssessor

Uncertain

2.7

MutationTaster

Benign

1.0

PrimateAI

Pathogenic

0.87

PROVEAN

Pathogenic

-4.7

REVEL

Uncertain

0.47

Sift

Uncertain

0.0020

Sift4G

Uncertain

0.019

Polyphen

1.0

Vest4

0.93

MutPred

0.83

Loss of MoRF binding (P = 0.0051);

MVP

0.64

MPC

0.75

ClinPred

0.88

GERP RS

5.5

Varity_R

0.51

gMVP

0.80

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over