3-39383735-A-G

Position:

chr3-39383735-A-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_017875.4(SLC25A38):c.11A>G(p.Asn4Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00181 in 1,614,022 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. N4N) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0015 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0019 ( 5 hom. )

Consequence

SLC25A38
NM_017875.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 4.08

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:

ENSG00000287780 (HGNC:):

ENSG00000287780 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009681672).

BP6

Variant 3-39383735-A-G is Benign according to our data. Variant chr3-39383735-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 777964.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=1}. Variant chr3-39383735-A-G is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00145 (221/152224) while in subpopulation NFE AF= 0.00271 (184/68004). AF 95% confidence interval is 0.00239. There are 0 homozygotes in gnomad4. There are 117 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC25A38	NM_017875.4 linkuse as main transcript	c.11A>G	p.Asn4Ser	missense_variant	1/7	ENST00000650617.1	NP_060345.2	Q96DW6
SLC25A38	NM_001354798.2 linkuse as main transcript	c.11A>G	p.Asn4Ser	missense_variant	1/6		NP_001341727.1
LOC105377644	XR_007096252.1 linkuse as main transcript	n.85+506T>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC25A38	ENST00000650617.1 linkuse as main transcript	c.11A>G	p.Asn4Ser	missense_variant	1/7		NM_017875.4	ENSP00000497532.1		Q96DW6

Frequencies

GnomAD3 genomes

AF:

0.00145

AC:

221

AN:

152106

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00105

Gnomad ASJ

AF:

0.00144

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000943

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00271

Gnomad OTH

AF:

0.00144

GnomAD3 exomes

AF:

0.00142

AC:

356

AN:

250928

Hom.:

AF XY:

0.00144

AC XY:

196

AN XY:

135762

show subpopulations

Gnomad AFR exome

AF:

0.000369

Gnomad AMR exome

AF:

0.000578

Gnomad ASJ exome

AF:

0.00119

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000980

Gnomad FIN exome

AF:

0.0000924

Gnomad NFE exome

AF:

0.00267

Gnomad OTH exome

AF:

0.00163

GnomAD4 exome

AF:

0.00185

AC:

2706

AN:

1461798

Hom.:

Cov.:

AF XY:

0.00183

AC XY:

1334

AN XY:

727208

show subpopulations

Gnomad4 AFR exome

AF:

0.000239

Gnomad4 AMR exome

AF:

0.000693

Gnomad4 ASJ exome

AF:

0.00119

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000464

Gnomad4 FIN exome

AF:

0.000243

Gnomad4 NFE exome

AF:

0.00227

Gnomad4 OTH exome

AF:

0.00149

GnomAD4 genome

AF:

0.00145

AC:

221

AN:

152224

Hom.:

Cov.:

AF XY:

0.00157

AC XY:

117

AN XY:

74442

show subpopulations

Gnomad4 AFR

AF:

0.000241

Gnomad4 AMR

AF:

0.00105

Gnomad4 ASJ

AF:

0.00144

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000943

Gnomad4 NFE

AF:

0.00271

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.00208

Hom.:

Bravo

AF:

0.00138

TwinsUK

AF:

0.00189

AC:

ALSPAC

AF:

0.00259

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00244

AC:

ExAC

AF:

0.00147

AC:

178

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00240

EpiControl

AF:

0.00302

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2023	SLC25A38: BP4 -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 25, 2024	See Variant Classification Assertion Criteria. -

Sideroblastic anemia 2

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.077

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.42

CADD

Benign

DANN

Benign

0.85

DEOGEN2

Benign

0.0091

T;T;.;.

Eigen

Benign

-0.76

Eigen_PC

Benign

-0.65

FATHMM_MKL

Uncertain

0.90

LIST_S2

Benign

0.49

.;T;T;T

M_CAP

Benign

0.034

MetaRNN

Benign

0.0097

T;T;T;T

MetaSVM

Benign

-0.95

MutationAssessor

Benign

0.34

N;N;.;.

PrimateAI

Benign

0.48

PROVEAN

Benign

0.13

N;.;.;.

REVEL

Benign

0.18

Sift

Uncertain

0.027

D;.;.;.

Sift4G

Benign

0.15

T;.;.;.

Polyphen

0.0

B;B;.;.

Vest4

0.12

MVP

0.71

MPC

0.19

ClinPred

0.033

GERP RS

3.1

Varity_R

0.060

gMVP

0.21

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

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