rs869320719

Variant names:

• chr3-39391483-ACT-A
• rs869320719
• NM_017875.4:c.324_325delCT

Variant summary

Our verdict is Pathogenic. The variant received 20 ACMG points: 20P and 0B. PVS1 PS3 PP5_Very_Strong

The NM_017875.4(SLC25A38):​c.324_325delCT​(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 (★★). ClinVar reports functional evidence for this variant: "SCV003289589: Experimental studies have shown that this premature translational stop signal affects SLC25A38 function (PMID:19412178).". 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:9
• Conservation: PhyloP100: 7.23
• Publications: 3 publications found

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]

SLC25A38 Gene-Disease associations (from GenCC):

• sideroblastic anemia 2

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, PanelApp Australia, G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• autosomal recessive sideroblastic anemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 20 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV003289589: Experimental studies have shown that this premature translational stop signal affects SLC25A38 function (PMID: 19412178).
• PP5: Variant 3-39391483-ACT-A is Pathogenic according to our data. Variant chr3-39391483-ACT-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 1119.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017875.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC25A38	NM_017875.4	MANE Select	c.324_325delCT	p.Tyr109LeufsTer43	frameshift	Exon 4 of 7	NP_060345.2	Q96DW6
	SLC25A38	NM_001354798.2		c.324_325delCT	p.Tyr109LeufsTer43	frameshift	Exon 4 of 6	NP_001341727.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC25A38	ENST00000650617.1	MANE Select	c.324_325delCT	p.Tyr109LeufsTer43	frameshift	Exon 4 of 7	ENSP00000497532.1	Q96DW6
	SLC25A38	ENST00000885743.1		c.324_325delCT	p.Tyr109LeufsTer43	frameshift	Exon 4 of 8	ENSP00000555802.1
	SLC25A38	ENST00000949226.1		c.324_325delCT	p.Tyr109LeufsTer43	frameshift	Exon 4 of 8	ENSP00000619285.1

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

GnomAD2 exomes AF: 0.000167 AC: 42 AN: 251474 AF XY: 0.000206

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 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

African (AFR) AF: 0.0000299 AC: 1 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86252

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5722

European-Non Finnish (NFE) AF: 0.000364 AC: 405 AN: 1112008

Other (OTH) AF: 0.0000994 AC: 6 AN: 60388

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

African (AFR) AF: 0.0000242 AC: 1 AN: 41352

American (AMR) AF: 0.00 AC: 0 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10540

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000397 AC: 27 AN: 67990

Other (OTH) AF: 0.00 AC: 0 AN: 2080

Alfa AF: 0.000304 Hom.: 0

Bravo AF: 0.000200

EpiCase AF: 0.000218

EpiControl AF: 0.000415

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
4	-	-	not provided (4)
4	-	-	Sideroblastic anemia 2 (4)
1	-	-	SLC25A38-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.2
Mutation Taster		=4/196	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs869320719; hg19: chr3-39432974;