rs397515429
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Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong
The NM_018344.6(SLC29A3):c.1157G>A(p.Arg386Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000112 in 1,614,122 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 Uncertain significance (★).
Frequency
Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000096 ( 0 hom. )
Consequence
SLC29A3
NM_018344.6 missense
NM_018344.6 missense
Scores
12
4
2
Clinical Significance
Conservation
PhyloP100: 10.0
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 Likely_pathogenic. Variant got 6 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.964
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
SLC29A3 | NM_018344.6 | c.1157G>A | p.Arg386Gln | missense_variant | 6/6 | ENST00000373189.6 | NP_060814.4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
SLC29A3 | ENST00000373189.6 | c.1157G>A | p.Arg386Gln | missense_variant | 6/6 | 1 | NM_018344.6 | ENSP00000362285 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000263 AC: 4AN: 152114Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000199 AC: 5AN: 251430Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135894
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GnomAD4 exome AF: 0.00000958 AC: 14AN: 1461890Hom.: 0 Cov.: 34 AF XY: 0.00000825 AC XY: 6AN XY: 727248
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GnomAD4 genome AF: 0.0000263 AC: 4AN: 152232Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74426
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ClinVar
Significance: Uncertain significance
Submissions summary: Pathogenic:1Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
H syndrome Pathogenic:1Uncertain:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Nov 15, 2012 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | May 17, 2022 | This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 386 of the SLC29A3 protein (p.Arg386Gln). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individuals with histiocytosis-lymphadenopathy plus syndrome and/or dysosteosclerosis (PMID: 22653152, 22875837). ClinVar contains an entry for this variant (Variation ID: 39870). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Uncertain
T;T;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
.;D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
M;M;.
MutationTaster
Benign
D
PrimateAI
Benign
T
PROVEAN
Uncertain
.;D;.
REVEL
Pathogenic
Sift
Pathogenic
.;D;.
Polyphen
D;D;.
Vest4
0.98
MutPred
Loss of catalytic residue at G381 (P = 0.2444);Loss of catalytic residue at G381 (P = 0.2444);.;
MVP
0.94
MPC
0.40
ClinPred
D
GERP RS
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Splicing
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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