10-71322827-C-T
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Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1PM2PP5
The NM_018344.6(SLC29A3):c.73C>T(p.Arg25Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000018 in 1,614,090 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 0.0000066 ( 0 hom., cov: 34)
Exomes 𝑓: 0.000019 ( 0 hom. )
Consequence
SLC29A3
NM_018344.6 stop_gained
NM_018344.6 stop_gained
Scores
1
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4
Clinical Significance
Conservation
PhyloP100: 0.775
Genes affected
SLC29A3 (HGNC:23096): (solute carrier family 29 member 3) This gene encodes a nucleoside transporter. The encoded protein plays a role in cellular uptake of nucleosides, nucleobases, and their related analogs. Mutations in this gene have been associated with H syndrome, which is characterized by cutaneous hyperpigmentation and hypertrichosis, hepatosplenomegaly, heart anomalies, and hypogonadism. A related disorder, PHID (pigmented hypertrichosis with insulin-dependent diabetes mellitus), has also been associated with mutations at this locus. Alternatively spliced transcript variants have been described.[provided by RefSeq, Mar 2010]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 11 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 30 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 10-71322827-C-T is Pathogenic according to our data. Variant chr10-71322827-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 212200.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=3, Uncertain_significance=1}.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SLC29A3 | NM_018344.6 | c.73C>T | p.Arg25Ter | stop_gained | 2/6 | ENST00000373189.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SLC29A3 | ENST00000373189.6 | c.73C>T | p.Arg25Ter | stop_gained | 2/6 | 1 | NM_018344.6 | P1 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152220Hom.: 0 Cov.: 34
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GnomAD3 exomes AF: 0.0000120 AC: 3AN: 250182Hom.: 0 AF XY: 0.0000148 AC XY: 2AN XY: 135362
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GnomAD4 exome AF: 0.0000192 AC: 28AN: 1461870Hom.: 0 Cov.: 35 AF XY: 0.0000261 AC XY: 19AN XY: 727236
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GnomAD4 genome AF: 0.00000657 AC: 1AN: 152220Hom.: 0 Cov.: 34 AF XY: 0.0000134 AC XY: 1AN XY: 74372
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:3Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
H syndrome Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | May 08, 2014 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | 3billion | May 22, 2022 | The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.001%). Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported to be associated with SLC29A3 related disorder (ClinVar ID: VCV000212200). The homozygous variant has been reported that each parent is heterozygous for the variant (3billion dataset). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 02, 2022 | For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 212200). This variant has not been reported in the literature in individuals affected with SLC29A3-related conditions. This variant is present in population databases (rs746408350, gnomAD 0.003%). This sequence change creates a premature translational stop signal (p.Arg25*) in the SLC29A3 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SLC29A3 are known to be pathogenic (PMID: 19336477, 20595384, 23406517, 25963354). - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Sep 01, 2016 | - - |
Computational scores
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Name
Calibrated prediction
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BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Uncertain
CADD
Pathogenic
DANN
Uncertain
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
N
MutationTaster
Benign
A
Vest4
0.30
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Splicing
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at