chr6-44254784-GAGC-G
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PM4_SupportingPP5
The NM_178148.4(SLC35B2):c.1218_1220del(p.Leu407del) variant causes a inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,882 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (no stars).
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000014 ( 0 hom. )
Consequence
SLC35B2
NM_178148.4 inframe_deletion
NM_178148.4 inframe_deletion
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 9.04
Genes affected
SLC35B2 (HGNC:16872): (solute carrier family 35 member B2) Sulfotransferases (e.g., SULT4A1; MIM 608359) use an activated form of sulfate, 3-prime-phosphoadenosine 5-prime-phosphosulfate (PAPS), as a common sulfate donor for sulfation of glycoproteins, proteoglycans, and glycolipids in the endoplasmic reticulum and Golgi apparatus. SLC35B2 is located in the microsomal membrane and transports PAPS from the cytosol, where it is synthesized, into the Golgi lumen (Kamiyama et al., 2003 [PubMed 12716889]).[supplied by OMIM, Mar 2008]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 4 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PM4
?
Nonframeshift variant in NON repetitive region in NM_178148.4. Strenght limited to Supporting due to length of the change: 1aa.
PP5
?
Variant 6-44254784-GAGC-G is Pathogenic according to our data. Variant chr6-44254784-GAGC-G is described in ClinVar as [Pathogenic]. Clinvar id is 984534.Status of the report is no_assertion_criteria_provided, 0 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SLC35B2 | NM_178148.4 | c.1218_1220del | p.Leu407del | inframe_deletion | 4/4 | ENST00000393812.4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SLC35B2 | ENST00000393812.4 | c.1218_1220del | p.Leu407del | inframe_deletion | 4/4 | 1 | NM_178148.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461882Hom.: 0 AF XY: 0.00000138 AC XY: 1AN XY: 727242
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GnomAD4 genome ? Cov.: 32
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Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:2
Revision: no assertion criteria provided
LINK: link
Submissions by phenotype
Leukodystrophy, hypomyelinating, 26, with chondrodysplasia Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Feb 28, 2023 | - - |
Primary bone dysplasia with multiple joint dislocations Pathogenic:1
Pathogenic, no assertion criteria provided | research | Cormier-Daire Lab, IMAGINE | Oct 09, 2020 | By whole exome sequencing, we identified a homozygous variant (c.1218_1220del, p.Leu407del) in SLC35B2 gene in one patient with autosomal recessive severe pre- and post-natal growth retardation, multiple dislocations, severe motor and intellectual disabilities and hypomyelinated leukodystrophy. This variant was absent from large population studies (such as gnomAD). SLC35B2 encodes an adenosine 3'-phospho 5'-phosphosulfate (PAPS) transporter, located at the Golgi apparatus membrane. By functional analyses, we showed that the mutation affects SLC35B2 mRNA expression and the protein subcellular localization most likely leading to a loss of function of the protein. Consistent with those results, we detected a proteoglycan sulfation impairment in SLC35B2 patient fibroblasts and serum, as compared to control individuals. Together, our data support that SLC35B2 is a new gene involved in the physiopathology of chondrodysplasia with multiple dislocations and brain anomalies, most likely through a proteoglycan sulfation defect and that the p.Leu407del variant meets our criteria to be classified as pathogenic (www.partners.org/personalizedmedicine/lmm) based upon segregation studies, absence from controls, and functional evidence. - |
Computational scores
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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