SLC25A38

protein-coding

solute carrier family 25 member 38, the group of Solute carrier family 25

Gene summary

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]

MANE transcript

NM_017875.4

Inheritance

ClinVar variants

P:63U:87B:42

Top phenotype

Anemia, sideroblastic 2, pyridoxine-refractory

gnomAD constraint

pLI —, LoF o/e 0.65

Max pathogenic AF

—

Genomic locus

chr3:39,383,370-39,397,351

External References & Databases

Ensembl (ENSG00000144659)

Transcript & Mutation Effects

hg38 • Region Span ~14.0 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

sideroblastic anemia 2STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0008785

Submitter: Genomics England PanelApp

autosomal recessive sideroblastic anemiaSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0016828

Submitter: Orphanet

sideroblastic anemia 2STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0008785

Submitter: PanelApp Australia

sideroblastic anemia 2DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0008785

Submitter: G2P

sideroblastic anemia 2STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0008785

Submitter: Labcorp Genetics (formerly Invitae)

sideroblastic anemia 2DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0008785

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

Anemia, sideroblastic 2, pyridoxine-refractoryAR

Manifestation: Hematologic

Intervention: Hematologic

Rationale: Individuals may have chronic, transfusion-dependent anemia refractory to pyridoxine, and diagnosis may allow early transfusion-based treatment

Refs: 19412178; 21393332

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to SLC25A38 variants in ClinVar

5 Conditions Cataloged

not providedTotal: 138

Sideroblastic anemia 2Total: 81

Inborn genetic diseasesTotal: 49

not specifiedTotal: 19

SLC25A38-related disorderTotal: 13

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_017875.4. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			3 clinvar	35 clinvar		38
missense	11 clinvar	9 clinvar	81 clinvar	7 clinvar		108
nonsense	9 clinvar	1 clinvar				10
start loss			2 clinvar			2
frameshift	18 clinvar	6 clinvar				24
splice donor/acceptor (+/-2bp)	7 clinvar	2 clinvar	1 clinvar			10
Total	45	18	87	42	0	192

Highest pathogenic variant AF is 0.00027327586

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 50 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_017875.4	RefSeq	NP_060345.2	7	MANE Select
ENST00000650617.1	Ensembl	ENSP00000497532.1	7	MANE Select
NM_001354798.2	RefSeq	NP_001341727.1	6	Standard
ENST00000431510.1	Ensembl	ENSP00000394244.1	5	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

heme biosynthetic process
erythrocyte differentiation
glycine import into mitochondrion

Molecular Function

glycine transmembrane transporter activity

Cellular Component

mitochondrion
mitochondrial inner membrane
integral component of membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000273158
Coding exons: 7
Length: 14004
Individuals with no LoFs: 125671
Homozygous LoFs: 0
Heterozygous LoFs: 77
Defined: 125748
p: 0.000306

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.263	162	172	0.943	0.0000104	1951
Missense (PolyPhen)		63	73.511	0.85701		816
Synonymous	0.537	60	65.5	0.916	0.00000392	646
Loss of Function	1.26	10	15.3	0.653	9.04e-7	166

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00043	0.00043	rare
Latino/Admixed American	0.00026	0.00026	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00016	0.00016	rare
Finnish	0.000046	0.000046	rare
European (Non-Finnish)	0.00046	0.00046	rare
South Asian	0.00013	0.00013	rare
Other	0.00016	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Mitochondrial glycine transporter that imports glycine into the mitochondrial matrix. Plays an important role in providing glycine for the first enzymatic step in heme biosynthesis, the condensation of glycine with succinyl-CoA to produce 5-aminolevulinate (ALA) in the mitochondrial matrix. Required during erythropoiesis. {ECO:0000255|HAMAP-Rule:MF_03064, ECO:0000269|PubMed:19412178, ECO:0000269|PubMed:27476175}.;

Recessive Scores

pRec: 0.117

Intolerance Scores

LoFtool: 0.653
RVIS EVS: 0
RVIS percentile EVS: 53.73

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.847

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium