6-44254784-GAGC-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PM4_Supporting PP5

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
• Clinical Significance: Pathogenic no assertion criteria provided P:2
• 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]

POLR1C (HGNC:):

ACMG classification

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

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461882 Hom.: 0 AF XY: 0.00000138 AC XY: 1 AN XY: 727242

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: no assertion criteria provided

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

Source: dbNSFP v4.3

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

Other links and lift over

dbSNP: rs760851221; hg19: chr6-44222521;