chr3-39383725-A-T

Variant names:

• chr3-39383725-A-T
• rs765685556
• NM_017875.4:c.1A>T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PVS1_Supporting PM2

The NM_017875.4(SLC25A38):​c.1A>T​(p.Met1?) variant causes a initiator codon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,736 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: SLC25A38 NM_017875.4 initiator_codon
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.74

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]

ENSG00000287780 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PVS1: Start lost variant, no pathogenic variants between lost start and next in-frame start position. Next in-frame start position is after 23 codons. Genomic position: 39383791. Lost 0.073 part of the original CDS.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC25A38	NM_017875.4	c.1A>T	p.Met1?	initiator_codon_variant	Exon 1 of 7	ENST00000650617.1	NP_060345.2
SLC25A38	NM_001354798.2	c.1A>T	p.Met1?	initiator_codon_variant	Exon 1 of 6		NP_001341727.1
LOC105377644	XR_007096252.1	n.85+516T>A		intron_variant	Intron 1 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC25A38	ENST00000650617.1	c.1A>T	p.Met1?	initiator_codon_variant	Exon 1 of 7		NM_017875.4	ENSP00000497532.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000797 AC: 2 AN: 250950 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135778

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000578

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461736 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727170

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Pathogenic	0.21
CADD	Benign	17
DANN	Benign	0.71
DEOGEN2	Benign	0.010	T;T;.;.
Eigen	Benign	-0.53
Eigen_PC	Benign	-0.51
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Uncertain	0.90	.;D;D;D
M_CAP	Uncertain	0.19	D
MetaRNN	Pathogenic	0.97	D;D;D;D
MetaSVM	Benign	-0.82	T
PROVEAN	Benign	-0.54	N;.;.;.
REVEL	Uncertain	0.43
Sift	Benign	0.083	T;.;.;.
Sift4G	Benign	0.19	T;.;.;.
Polyphen		0.0	B;B;.;.
Vest4		0.79
MutPred		0.99		Gain of catalytic residue at M1 (P = 0.097);Gain of catalytic residue at M1 (P = 0.097);Gain of catalytic residue at M1 (P = 0.097);Gain of catalytic residue at M1 (P = 0.097);
MVP		0.77
ClinPred		0.72	D
GERP RS		3.1
Varity_R		0.39
gMVP		0.27

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: rs765685556; hg19: chr3-39425216;