rs587776961
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PM2PP3_ModeratePP5_Very_Strong
The NM_005660.3(SLC35A2):c.991G>A(p.Val331Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Genomes: not found (cov: 24)
Exomes 𝑓: 0.0 ( 0 hom. 0 hem. )
Failed GnomAD Quality Control
Consequence
SLC35A2
NM_005660.3 missense
NM_005660.3 missense
Scores
6
8
3
Clinical Significance
Conservation
PhyloP100: 3.49
Genes affected
SLC35A2 (HGNC:11022): (solute carrier family 35 member A2) This gene encodes a member of the nucleotide-sugar transporter family. The encoded protein is a multi-pass membrane protein. It transports UDP-galactose from the cytosol into Golgi vesicles, where it serves as a glycosyl donor for the generation of glycans. Mutations in this gene cause congenital disorder of glycosylation type IIm (CDG2M). Multiple alternatively spliced transcript variants encoding distinct isoforms have been found for this gene. [provided by RefSeq, Oct 2014]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 14 ACMG points.
PM1
?
In a transmembrane_region Helical (size 20) in uniprot entity S35A2_HUMAN there are 4 pathogenic changes around while only 1 benign (80%) in NM_005660.3
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.863
PP5
?
Variant X-48904918-C-T is Pathogenic according to our data. Variant chrX-48904918-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 50364.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-48904918-C-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SLC35A2 | NM_005660.3 | c.991G>A | p.Val331Ile | missense_variant | 4/5 | ENST00000247138.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SLC35A2 | ENST00000247138.11 | c.991G>A | p.Val331Ile | missense_variant | 4/5 | 1 | NM_005660.3 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 24
GnomAD3 genomes
?
Cov.:
24
GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 1096817Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 362195
GnomAD4 exome
Data not reliable, filtered out with message: AC0
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0
AN:
1096817
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Cov.:
31
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0
AN XY:
362195
Gnomad4 AFR exome
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GnomAD4 genome ? Cov.: 24
GnomAD4 genome
?
Cov.:
24
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
SLC35A2-congenital disorder of glycosylation Pathogenic:4
Pathogenic, no assertion criteria provided | research | University of Washington Center for Mendelian Genomics, University of Washington | Nov 14, 2013 | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Apr 04, 2013 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Feb 10, 2022 | This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with early infantile epileptic encephalopathy and/or SLC35A2-CDG (PMID: 23561849, 28771251, 29907092, 30746764; Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 50364). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). For these reasons, this variant has been classified as Pathogenic. This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 331 of the SLC35A2 protein (p.Val331Ile). - |
Pathogenic, criteria provided, single submitter | clinical testing | Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego | Aug 18, 2020 | This variant has been previously reported as a de novo change in multiple, unrelated, patients with congenital disorder of glycosylation (PMID: 23561849, 28771251, 29907092, 30746764). It is absent from the gnomAD population database and thus is presumed to be rare. The c.991G>A (p.Val331Ile) variant affects a highly conserved amino acid; however, in silico tools used to predict the effect of this variant on protein function yield discordant results. Analysis of the parental samples was negative for the variant, indicating this variant likely occurred as a de novo event. Based on the available evidence, the c.991G>A (p.Val331Ile) variant is classified as Pathogenic. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Mar 29, 2022 | Published functional studies found this variant is associated with reduced UDP-galactose transport (Ng BG et al., 2013); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 27743886, 32820034, 23561849, 25778940, 28771251, 29907092, 30746764) - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Benign
T;.;.;T;.
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D;D;D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D;D
MetaSVM
Uncertain
T
MutationAssessor
Uncertain
M;M;.;.;.
MutationTaster
Benign
D;D;D;D;D;D;D
PrimateAI
Uncertain
T
PROVEAN
Benign
N;N;.;.;N
REVEL
Uncertain
Sift
Pathogenic
D;D;.;.;D
Sift4G
Uncertain
D;D;T;D;D
Polyphen
D;D;.;D;.
Vest4
MutPred
Gain of sheet (P = 0.1945);Gain of sheet (P = 0.1945);.;.;.;
MVP
MPC
ClinPred
D
GERP RS
BranchPoint Hunter
?
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at