rs869320719

Positions:

• chr3-39391483-ACT-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_017875.4(SLC25A38):​c.324_325delCT​(p.Tyr109fs) 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 (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.00018 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00028 (0 hom.)
• Consequence: SLC25A38 NM_017875.4 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8
• 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]

ACMG classification

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_325delCT	p.Tyr109fs	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_325delCT	p.Tyr109fs	frameshift_variant	4/7		NM_017875.4	ENSP00000497532.1

Frequencies

GnomAD3 genomes AF: 0.000184 AC: 28 AN: 151926 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000397

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000167 AC: 42 AN: 251474 Hom.: 0 AF XY: 0.000206 AC XY: 28 AN XY: 135910

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000360

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000283 AC: 413 AN: 1461828 Hom.: 0 AF XY: 0.000303 AC XY: 220 AN XY: 727210

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000364

Gnomad4 OTH exome AF: 0.0000994

GnomAD4 genome AF: 0.000184 AC: 28 AN: 151926 Hom.: 0 Cov.: 33 AF XY: 0.000108 AC XY: 8 AN XY: 74198

Gnomad4 AFR AF: 0.0000242

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000397

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000304 Hom.: 0

Bravo AF: 0.000200

EpiCase AF: 0.000218

EpiControl AF: 0.000415

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:4

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 -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	May 27, 2022	- -

Sideroblastic anemia 2 Pathogenic:3

Pathogenic, criteria provided, single submitter	research	Mark Fleming Laboratory, Boston Children's Hospital	Jun 01, 2021	- -
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. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 01, 2009	- -

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

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs869320719; hg19: chr3-39432974;