NM_007255.3:c.50+1G>A

Variant names:

• chr5-177600261-G-A
• NM_007255.3:c.50+1G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PVS1_Strong PM2

The NM_007255.3(B4GALT7):​c.50+1G>A variant causes a splice donor, intron change. The variant allele was found at a frequency of 0.000000834 in 1,199,404 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 8.3e-7 (0 hom.)
• Consequence: B4GALT7 NM_007255.3 splice_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.22
• Publications: 0 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, Labcorp Genetics (formerly Invitae), PanelApp Australia, G2P, Ambry Genetics
• Ehlers-Danlos syndrome, spondylodysplastic type

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.13109756 fraction of the gene. Cryptic splice site detected, with MaxEntScore 4.7, offset of 13, new splice context is: gcgGTgggc. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
B4GALT7	NM_007255.3	c.50+1G>A		splice_donor_variant, intron_variant	Intron 1 of 5	ENST00000029410.10	NP_009186.1
B4GALT7	XM_047416681.1	c.-1061+1G>A		splice_donor_variant, intron_variant	Intron 1 of 6		XP_047272637.1
B4GALT7	XM_047416682.1	c.-346+1G>A		splice_donor_variant, intron_variant	Intron 1 of 6		XP_047272638.1
B4GALT7	XM_047416680.1	c.-2225G>A		upstream_gene_variant			XP_047272636.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
B4GALT7	ENST00000029410.10	c.50+1G>A		splice_donor_variant, intron_variant	Intron 1 of 5	1	NM_007255.3	ENSP00000029410.5

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 8.34e-7 AC: 1 AN: 1199404 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 584114

African (AFR) AF: 0.00 AC: 0 AN: 24328

American (AMR) AF: 0.00 AC: 0 AN: 16522

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19094

East Asian (EAS) AF: 0.00 AC: 0 AN: 27204

South Asian (SAS) AF: 0.00 AC: 0 AN: 54558

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 27962

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3410

European-Non Finnish (NFE) AF: 0.00000102 AC: 1 AN: 978078

Other (OTH) AF: 0.00 AC: 0 AN: 48248

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Uncertain:1

Aug 21, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant has not been reported in the literature in individuals affected with B4GALT7-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 1 of the B4GALT7 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), however the current clinical and genetic evidence is not sufficient to establish whether loss-of-function variants in B4GALT7 cause disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.60	D
BayesDel_noAF	Pathogenic	0.19
CADD	Pathogenic	34
DANN	Uncertain	0.99
Eigen	Pathogenic	0.95
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Uncertain	0.89	D
PhyloP100		4.2
GERP RS		4.0
PromoterAI		-0.72	Under-expression
Mutation Taster		=3/97	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.99		Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

hg19: chr5-177027262;