rs121434363
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2PP3_StrongPP5
The NM_001128225.3(SLC39A13):c.221G>A(p.Gly74Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000248 in 1,614,042 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 0.000020 ( 0 hom., cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )
Consequence
SLC39A13
NM_001128225.3 missense
NM_001128225.3 missense
Scores
8
9
2
Clinical Significance
Conservation
PhyloP100: 7.79
Genes affected
SLC39A13 (HGNC:20859): (solute carrier family 39 member 13) This gene encodes a member of the LIV-1 subfamily of the ZIP transporter family. The encoded transmembrane protein functions as a zinc transporter. Mutations in this gene have been associated with the spondylocheiro dysplastic form of Ehlers-Danlos syndrome. Alternate transcript variants have been found for this gene. [provided by RefSeq, Jan 2016]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.958
PP5
Variant 11-47410315-G-A is Pathogenic according to our data. Variant chr11-47410315-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 2133.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=1}.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
SLC39A13 | NM_001128225.3 | c.221G>A | p.Gly74Asp | missense_variant | 2/10 | ENST00000362021.9 | NP_001121697.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
SLC39A13 | ENST00000362021.9 | c.221G>A | p.Gly74Asp | missense_variant | 2/10 | 1 | NM_001128225.3 | ENSP00000354689.4 |
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152170Hom.: 0 Cov.: 32
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GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461872Hom.: 0 Cov.: 73 AF XY: 0.00 AC XY: 0AN XY: 727244
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GnomAD4 genome AF: 0.0000197 AC: 3AN: 152170Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74344
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:2Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Ehlers-Danlos syndrome, spondylocheirodysplastic type Pathogenic:1Uncertain:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Jan 01, 2008 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jul 19, 2022 | This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 74 of the SLC39A13 protein (p.Gly74Asp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with spondylodysplastic type Ehlers-Danlos syndrome (PMID: 18985159). It has also been observed to segregate with disease in related individuals. This variant is also known as G64D. ClinVar contains an entry for this variant (Variation ID: 2133). 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"). Experimental studies have shown that this missense change affects SLC39A13 function (PMID: 18985159, 25007800). 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. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Mar 20, 2024 | Published functional studies demonstrate protein instability and rapid degredation (PMID: 25007800); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 18985159, 32295219, 25007800) - |
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;.;T;T;.;.;.;T
Eigen
Pathogenic
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D;D;D;D;D;D;D;D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D;D;D;D;D;D;D;D
MetaSVM
Uncertain
T
MutationAssessor
Uncertain
.;.;.;.;M;M;.;.;.
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;D;D;D;D;D;D;D;D
REVEL
Pathogenic
Sift
Uncertain
D;D;D;D;D;D;D;D;D
Sift4G
Uncertain
D;D;D;D;D;D;D;D;D
Polyphen
1.0
.;.;.;.;D;D;.;.;D
Vest4
MutPred
Gain of helix (P = 0.027);Gain of helix (P = 0.027);Gain of helix (P = 0.027);Gain of helix (P = 0.027);Gain of helix (P = 0.027);Gain of helix (P = 0.027);Gain of helix (P = 0.027);Gain of helix (P = 0.027);Gain of helix (P = 0.027);
MVP
MPC
1.3
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
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