3-39383735-A-G

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:2
• Conservation: PhyloP100: 4.08

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -9 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=2, Uncertain_significance=2}. 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC25A38	NM_017875.4	c.11A>G	p.Asn4Ser	missense_variant	1/7	ENST00000650617.1
LOC105377644	XR_007096252.1	n.85+506T>C		intron_variant, non_coding_transcript_variant
SLC25A38	NM_001354798.2	c.11A>G	p.Asn4Ser	missense_variant	1/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC25A38	ENST00000650617.1	c.11A>G	p.Asn4Ser	missense_variant	1/7		NM_017875.4	P1
	ENST00000655387.1	n.60+506T>C		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.00145 AC: 221 AN: 152106 Hom.: 0 Cov.: 33

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.: 0 AF XY: 0.00144 AC XY: 196 AN XY: 135762

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.: 5 Cov.: 31 AF XY: 0.00183 AC XY: 1334 AN XY: 727208

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.: 0 Cov.: 33 AF XY: 0.00157 AC XY: 117 AN XY: 74442

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.: 1

Bravo AF: 0.00138

TwinsUK AF: 0.00189 AC: 7

ALSPAC AF: 0.00259 AC: 10

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00244 AC: 21

ExAC AF: 0.00147 AC: 178

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00240

EpiControl AF: 0.00302

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Nov 15, 2021	Has not been previously published as pathogenic or benign to our knowledge; In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function -
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	Invitae	Jan 29, 2024	- -

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	T
BayesDel_noAF	Benign	-0.42
Cadd	Benign	22
Dann	Benign	0.85
DEOGEN2	Benign	0.0091	T;T;.;.
Eigen	Benign	-0.76
Eigen_PC	Benign	-0.65
FATHMM_MKL	Uncertain	0.90	D
M_CAP	Benign	0.034	D
MetaRNN	Benign	0.0097	T;T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.34	N;N;.;.
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.48	T
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	T
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

Other links and lift over

dbSNP: rs61995897; hg19: chr3-39425226;