chr3-39383433-G-A

Position:

• chr3-39383433-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_017875.4(SLC25A38):​c.-292G>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 0.013 in 474,290 control chromosomes in the GnomAD database, including 69 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.011 (17 hom., cov: 33)
  • Exomes 𝑓: 0.014 (52 hom.)
• Consequence: SLC25A38 NM_017875.4 5_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 0.725

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 3-39383433-G-A is Benign according to our data. Variant chr3-39383433-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 345135.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0113 (1729/152384) while in subpopulation NFE AF= 0.0185 (1257/68044). AF 95% confidence interval is 0.0176. There are 17 homozygotes in gnomad4. There are 776 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 17 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC25A38	NM_017875.4	c.-292G>A		5_prime_UTR_variant	1/7	ENST00000650617.1	NP_060345.2
LOC105377644	XR_007096252.1	n.86-389C>T		intron_variant, non_coding_transcript_variant
SLC25A38	NM_001354798.2	c.-292G>A		5_prime_UTR_variant	1/6		NP_001341727.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC25A38	ENST00000650617.1	c.-292G>A		5_prime_UTR_variant	1/7		NM_017875.4	ENSP00000497532	P1
	ENST00000655387.1	n.61-389C>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.0114 AC: 1732 AN: 152266 Hom.: 17 Cov.: 33

Gnomad AFR AF: 0.00330

Gnomad AMI AF: 0.00658

Gnomad AMR AF: 0.0105

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00745

Gnomad FIN AF: 0.00922

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0185

Gnomad OTH AF: 0.0124

GnomAD4 exome AF: 0.0137 AC: 4424 AN: 321906 Hom.: 52 Cov.: 0 AF XY: 0.0138 AC XY: 2359 AN XY: 170982

Gnomad4 AFR exome AF: 0.00342

Gnomad4 AMR exome AF: 0.00694

Gnomad4 ASJ exome AF: 0.00290

Gnomad4 EAS exome AF: 0.0000525

Gnomad4 SAS exome AF: 0.00894

Gnomad4 FIN exome AF: 0.00712

Gnomad4 NFE exome AF: 0.0187

Gnomad4 OTH exome AF: 0.0113

GnomAD4 genome AF: 0.0113 AC: 1729 AN: 152384 Hom.: 17 Cov.: 33 AF XY: 0.0104 AC XY: 776 AN XY: 74516

Gnomad4 AFR AF: 0.00327

Gnomad4 AMR AF: 0.0104

Gnomad4 ASJ AF: 0.00288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00725

Gnomad4 FIN AF: 0.00922

Gnomad4 NFE AF: 0.0185

Gnomad4 OTH AF: 0.0123

Alfa AF: 0.0115 Hom.: 3

Bravo AF: 0.0110

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

X-linked sideroblastic anemia 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 07, 2018

- -

Sideroblastic anemia 2 Benign:1

Likely benign, 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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	7.2
DANN	Benign	0.82
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

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: rs142441701; hg19: chr3-39424924;