rs200503833
Variant names:
Your query was ambiguous. Multiple possible variants found:
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 7P and 1B. PVS1_StrongPM2PP5BS1_Supporting
The NM_007255.3(B4GALT7):c.38G>A(p.Trp13*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000618 in 1,385,202 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 Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.00026 ( 0 hom., cov: 31)
Exomes 𝑓: 0.00066 ( 0 hom. )
Consequence
B4GALT7
NM_007255.3 stop_gained
NM_007255.3 stop_gained
Scores
4
1
2
Clinical Significance
Conservation
PhyloP100: 1.99
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]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 13 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 5-177600248-G-A is Pathogenic according to our data. Variant chr5-177600248-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 282261.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=3, Pathogenic=2, Likely_pathogenic=2}.
BS1
Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.000663 (817/1233122) while in subpopulation NFE AF= 0.000793 (789/995320). AF 95% confidence interval is 0.000746. There are 0 homozygotes in gnomad4_exome. There are 375 alleles in male gnomad4_exome subpopulation. Median coverage is 30. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| B4GALT7 | NM_007255.3 | c.38G>A | p.Trp13* | stop_gained | Exon 1 of 6 | ENST00000029410.10 | NP_009186.1 | |
| B4GALT7 | XM_047416681.1 | c.-1073G>A | 5_prime_UTR_variant | Exon 1 of 7 | XP_047272637.1 | |||
| B4GALT7 | XM_047416682.1 | c.-358G>A | 5_prime_UTR_variant | Exon 1 of 7 | XP_047272638.1 |
Ensembl
Frequencies
GnomAD3 genomes 0.000256 AC: 39AN: 152080Hom.: 0 Cov.: 31
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GnomAD3 exomes AF: 0.000209 AC: 13AN: 62262Hom.: 0 AF XY: 0.000191 AC XY: 7AN XY: 36736
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GnomAD4 exome AF: 0.000663 AC: 817AN: 1233122Hom.: 0 Cov.: 30 AF XY: 0.000622 AC XY: 375AN XY: 602812
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GnomAD4 genome 0.000256 AC: 39AN: 152080Hom.: 0 Cov.: 31 AF XY: 0.000229 AC XY: 17AN XY: 74274
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:4Uncertain:3
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Pathogenic:2Uncertain:1
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Nov 11, 2024 | Has not been previously reported in association with a B4GALT7-related disorder to our knowledge; Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 31345219) - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Aug 14, 2015 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Jun 22, 2023 | PVS1 - |
Ehlers-Danlos syndrome, spondylodysplastic type, 1 Pathogenic:2
| Likely pathogenic, criteria provided, single submitter | research | HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology | Nov 13, 2023 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Feb 02, 2022 | Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Ehlers-Danlos syndrome, spondylodysplastic type, 1 (MIM#130070) (PMID: 31278392). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v3) <0.01 for a recessive condition (39 heterozygotes, 0 homozygotes). (SP) 0703 - Other NMD-predicted variants comparable to the one identified in this case have moderate previous evidence for pathogenicity. These two variants have been reported as likely pathogenic, and have been reported in several patients with spondodylodysplastic-Ehlers-Danlos syndrome (EDS) (PMID: 31614862, ClinVar, Decipher). (SP) 0808 - Previous reports of pathogenicity for this variant are conflicting. This variant has been reported as both likely pathogenic and as a VUS (ClinVar and NTD Genetics). It has also been observed as homozygous in an individual with global developmental delay, broad-based gait and stereotypy, but subsequently classified as benign with no other information provided (DECIPHER). (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign - |
Ehlers-Danlos syndrome progeroid type Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Aug 21, 2022 | This sequence change creates a premature translational stop signal (p.Trp13*) in the B4GALT7 gene. It is expected to result in an absent or disrupted protein product. However, the current clinical and genetic evidence is not sufficient to establish whether loss-of-function variants in B4GALT7 cause disease. This variant is present in population databases (rs200503833, gnomAD 0.04%). This variant has not been reported in the literature in individuals affected with B4GALT7-related conditions. ClinVar contains an entry for this variant (Variation ID: 282261). 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. - |
Ehlers-Danlos syndrome Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Genome Diagnostics Laboratory, The Hospital for Sick Children | Dec 01, 2019 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Benign
N
Vest4
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at