3-39391956-G-C

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PP3_ModeratePP5

The NM_017875.4(SLC25A38):c.560G>C(p.Arg187Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000743 in 1,614,086 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 0.0000066 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000075 ( 0 hom. )

Consequence

SLC25A38
NM_017875.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3U:1

Conservation

PhyloP100: 9.52

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 5 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.933

PP5

Variant 3-39391956-G-C is Pathogenic according to our data. Variant chr3-39391956-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1120.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1, Pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC25A38	NM_017875.4 link	c.560G>C	p.Arg187Pro	missense_variant	Exon 5 of 7	ENST00000650617.1	NP_060345.2	Q96DW6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC25A38	ENST00000650617.1 link	c.560G>C	p.Arg187Pro	missense_variant	Exon 5 of 7		NM_017875.4	ENSP00000497532.1		Q96DW6

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152204

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000796

AC:

AN:

251384

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135860

show subpopulations

Gnomad AFR exome

AF:

0.0000615

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:

0.00000880

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000752

AC:

AN:

1461882

Hom.:

Cov.:

AF XY:

0.00000688

AC XY:

AN XY:

727244

show subpopulations

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:

0.00

Gnomad4 NFE exome

AF:

0.00000899

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152204

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74364

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Sideroblastic anemia 2

Pathogenic:3

Jun 01, 2021

Mark Fleming Laboratory, Boston Children's Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Nov 09, 2018

Illumina Laboratory Services, Illumina

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The SLC25A38 c.560G>C (p.Arg187Pro) missense variant has been reported in three studies and has been found in five individuals, including a sibling pair, with congenital sideroblastic anemia. One individual was homozygous for the variant while the others were compound heterozygous for the variant (Guernsey et al. 2009; Kannengiesser et al. 2011; An et al. 2015). The SLC25A38 p.Arg187Pro variant was absent from 251 healthy population controls but is reported at a frequency of 0.000116 in the European American population of the Exome Sequencing Project, however this is based on a single allele in a region of good sequencing coverage and the variant is presumed to be rare. Based on the evidence, the SLC25A38 p.Arg187Pro variant is classified as likely pathogenic for pyridoxine-refractory sideroblastic anemia. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Jun 01, 2009

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided

Uncertain:1

Aug 21, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 187 of the SLC25A38 protein (p.Arg187Pro). This variant is present in population databases (rs121918331, gnomAD 0.007%). This missense change has been observed in individual(s) with congenital sideroblastic anemia (PMID: 19412178). This variant is also known as c.937G>C. ClinVar contains an entry for this variant (Variation ID: 1120). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.33

BayesDel_noAF

Pathogenic

0.42

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.65

D;D;.;.;.;.

Eigen

Pathogenic

0.83

Eigen_PC

Uncertain

0.65

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Pathogenic

0.98

.;D;D;D;D;D

M_CAP

Pathogenic

0.38

MetaRNN

Pathogenic

0.93

D;D;D;D;D;D

MetaSVM

Pathogenic

0.95

MutationAssessor

Pathogenic

4.8

H;H;.;.;.;.

PrimateAI

Uncertain

0.69

PROVEAN

Pathogenic

-6.6

D;.;.;.;.;.

REVEL

Pathogenic

0.84

Sift

Pathogenic

0.0

D;.;.;.;.;.

Sift4G

Pathogenic

0.0

D;.;.;.;.;.

Polyphen

1.0

D;D;.;.;.;.

Vest4

0.99

MVP

0.93

MPC

1.1

ClinPred

1.0

GERP RS

4.0

Varity_R

0.99

gMVP

0.97

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.090

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over