rs869320719
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Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_017875.4(SLC25A38):βc.324_325delβ(p.Tyr109LeufsTer43) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000273 in 1,613,754 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (β β ). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: π 0.00018 ( 0 hom., cov: 33)
Exomes π: 0.00028 ( 0 hom. )
Consequence
SLC25A38
NM_017875.4 frameshift
NM_017875.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 7.23
Genes affected
SLC25A38 (HGNC:26054): (solute carrier family 25 member 38) This gene is a member of the mitochondrial carrier family. The encoded protein is required during erythropoiesis and is important for the biosynthesis of heme. Mutations in this gene are the cause of autosomal congenital sideroblastic anemia (anemia, sideroblastic, 2, pyridoxine-refractory). A related pseudogene is found on chromosome 1. [provided by RefSeq, Aug 2017]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 3-39391483-ACT-A is Pathogenic according to our data. Variant chr3-39391483-ACT-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1119.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
SLC25A38 | NM_017875.4 | c.324_325del | p.Tyr109LeufsTer43 | frameshift_variant | 4/7 | ENST00000650617.1 | NP_060345.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
SLC25A38 | ENST00000650617.1 | c.324_325del | p.Tyr109LeufsTer43 | frameshift_variant | 4/7 | NM_017875.4 | ENSP00000497532 | P1 |
Frequencies
GnomAD3 genomes AF: 0.000184 AC: 28AN: 151926Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.000167 AC: 42AN: 251474Hom.: 0 AF XY: 0.000206 AC XY: 28AN XY: 135910
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GnomAD4 exome AF: 0.000283 AC: 413AN: 1461828Hom.: 0 AF XY: 0.000303 AC XY: 220AN XY: 727210
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GnomAD4 genome AF: 0.000184 AC: 28AN: 151926Hom.: 0 Cov.: 33 AF XY: 0.000108 AC XY: 8AN XY: 74198
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:8
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | Clinical Genetics Laboratory, Skane University Hospital Lund | May 27, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 28, 2023 | This sequence change creates a premature translational stop signal (p.Tyr109Leufs*43) in the SLC25A38 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SLC25A38 are known to be pathogenic (PMID: 19412178, 25985931). This variant is present in population databases (rs535344665, gnomAD 0.04%). This premature translational stop signal has been observed in individuals with congenital sideroblastic anemia (PMID: 19412178, 21393332). ClinVar contains an entry for this variant (Variation ID: 1119). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects SLC25A38 function (PMID: 19412178). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Dec 10, 2021 | Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 28772256, 19412178, 27753142, 21393332, 31589614) - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Dec 01, 2023 | SLC25A38: PM3:Very Strong, PVS1, PM2:Supporting - |
Sideroblastic anemia 2 Pathogenic:3
Pathogenic, criteria provided, single submitter | research | Mark Fleming Laboratory, Boston Children's Hospital | Jun 01, 2021 | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Jun 01, 2009 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | 3billion | - | The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.017%). The variant is 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 at least twice as pathogenic without evidence for the classification (ClinVar ID: VCV000001119 / PMID: 19412178). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. - |
SLC25A38-related disorder Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Dec 04, 2018 | The SLC25A38 c.324_325delCT (p.Tyr109LeufsTer43) frameshift variant is also reported as c.698_699delCT (p.Leu108fs) in literature. This variant has been reported in at least two studies, in which it is found in a total of six unrelated individuals with congenital sideroblastic anemia, including in two in a homozygous state and in four in a compound heterozygous state with a second missense or truncating variant (Guernsey et al. 2009; Kannengiesser et al. 2011). This variant is not reported in individuals with pyridoxine-refractory sideroblastic anemia. Control data are unavailable for this variant, which is reported at a frequency of 0.001454 in the European American population of the Exome Sequencing Project. Based on the collective evidence, the p.Tyr109LeufsTer43 variant is classified as likely pathogenic for SLC25A38-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. - |
Computational scores
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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