3-39383564-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The NM_017875.4(SLC25A38):c.-161G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00144 in 721,226 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0012 (3 hom., cov: 33)
  • Exomes 𝑓: 0.0015 (8 hom.)
• Consequence: SLC25A38 NM_017875.4 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: -0.230

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 (BayesDel_noAF=-0.75).
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00125 (190/152350) while in subpopulation AMR AF= 0.0015 (23/15308). AF 95% confidence interval is 0.00103. There are 3 homozygotes in gnomad4. There are 95 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC25A38	NM_017875.4	c.-161G>A		5_prime_UTR_variant	1/7	ENST00000650617.1
LOC105377644	XR_007096252.1	n.86-520C>T		intron_variant, non_coding_transcript_variant
SLC25A38	NM_001354798.2	c.-161G>A		5_prime_UTR_variant	1/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC25A38	ENST00000650617.1	c.-161G>A		5_prime_UTR_variant	1/7		NM_017875.4	P1
	ENST00000655387.1	n.61-520C>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.00125 AC: 190 AN: 152232 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.0285

Gnomad AMR AF: 0.00150

Gnomad ASJ AF: 0.0207

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.000720

Gnomad OTH AF: 0.00287

GnomAD4 exome AF: 0.00149 AC: 845 AN: 568876 Hom.: 8 Cov.: 8 AF XY: 0.00151 AC XY: 454 AN XY: 300522

Gnomad4 AFR exome AF: 0.000480

Gnomad4 AMR exome AF: 0.00235

Gnomad4 ASJ exome AF: 0.0207

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000980

Gnomad4 FIN exome AF: 0.0000225

Gnomad4 NFE exome AF: 0.000816

Gnomad4 OTH exome AF: 0.00265

GnomAD4 genome AF: 0.00125 AC: 190 AN: 152350 Hom.: 3 Cov.: 33 AF XY: 0.00128 AC XY: 95 AN XY: 74508

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.00150

Gnomad4 ASJ AF: 0.0207

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00124

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000720

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00169 Hom.: 0

Bravo AF: 0.00158

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

Submissions by phenotype

Refractory anemia with ringed sideroblasts (clinical) Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Sideroblastic anemia 2 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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
BayesDel_noAF	Benign	-0.75
Cadd	Benign	7.7
Dann	Benign	0.94

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: rs528990278; hg19: chr3-39425055;