chr5-177607309-C-T
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PM2PP3_ModeratePP5_Very_Strong
The NM_007255.3(B4GALT7):c.421C>T(p.Arg141Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000125 in 1,608,308 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 (★★). Synonymous variant affecting the same amino acid position (i.e. R141R) has been classified as Likely benign.
Frequency
Consequence
NM_007255.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
B4GALT7 | NM_007255.3 | c.421C>T | p.Arg141Trp | missense_variant | 3/6 | ENST00000029410.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
B4GALT7 | ENST00000029410.10 | c.421C>T | p.Arg141Trp | missense_variant | 3/6 | 1 | NM_007255.3 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000788 AC: 12AN: 152242Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000332 AC: 8AN: 240716Hom.: 0 AF XY: 0.0000384 AC XY: 5AN XY: 130306
GnomAD4 exome AF: 0.000130 AC: 189AN: 1455948Hom.: 0 Cov.: 31 AF XY: 0.000123 AC XY: 89AN XY: 723836
GnomAD4 genome AF: 0.0000788 AC: 12AN: 152360Hom.: 0 Cov.: 33 AF XY: 0.0000537 AC XY: 4AN XY: 74504
ClinVar
Submissions by phenotype
Ehlers-Danlos syndrome progeroid type Pathogenic:2
Pathogenic, no assertion criteria provided | literature only | OMIM | Dec 22, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Sep 19, 2023 | This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 141 of the B4GALT7 protein (p.Arg141Trp). This variant is present in population databases (rs187063864, gnomAD 0.008%). This missense change has been observed in individual(s) with spondylodysplastic Ehlers-Danlos syndrome (PMID: 26940150, 30914273). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 253108). 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) performed at Invitae indicates that this missense variant is expected to disrupt B4GALT7 protein function. For these reasons, this variant has been classified as Pathogenic. - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Mar 19, 2018 | The R141W variant in the B4GALT7 gene has been reported previously in trans with another variant in an individual with disproportionate short-limbed short stature, joint hypermobility, relative macrocephaly, and dysmorphic features (Fitzgerald et al., 2015; Salter et al., 2016). The R141W variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R141W variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret R141W as a likely pathogenic variant. - |
Ehlers-Danlos syndrome, spondylodysplastic type, 1 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Dec 21, 2022 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at