chr8-103414874-G-A

Position:

• chr8-103414874-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_030780.5(SLC25A32):​c.64C>T​(p.Arg22Trp) variant causes a missense change. The variant allele was found at a frequency of 0.00000342 in 1,460,862 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: SLC25A32 NM_030780.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 4.38

Genes affected

SLC25A32 (HGNC:29683): (solute carrier family 25 member 32) This gene encodes a member of the P(I/L)W subfamily of mitochondrial carrier family transport proteins. The encoded protein transports folate across the inner mitochondrial membrane. Alternatively spliced transcript variants have been described. [provided by RefSeq, Mar 2013]

DCAF13 (HGNC:24535): (DDB1 and CUL4 associated factor 13) Enables estrogen receptor binding activity. Predicted to be involved in maturation of SSU-rRNA from tricistronic rRNA transcript (SSU-rRNA, 5.8S rRNA, LSU-rRNA). Located in several cellular components, including centrosome; cytosol; and nuclear lumen. Part of Cul4-RING E3 ubiquitin ligase complex. [provided by Alliance of Genome Resources, Apr 2022]

ENSG00000285982 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.847

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC25A32	NM_030780.5	c.64C>T	p.Arg22Trp	missense_variant	1/7	ENST00000297578.9	NP_110407.2
SLC25A32	NR_102337.2	n.234C>T		non_coding_transcript_exon_variant	1/6
SLC25A32	NR_102338.2	n.234C>T		non_coding_transcript_exon_variant	1/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC25A32	ENST00000297578.9	c.64C>T	p.Arg22Trp	missense_variant	1/7	1	NM_030780.5	ENSP00000297578.4
ENSG00000285982	ENST00000649416.1	c.2-7090C>T		intron_variant				ENSP00000496817.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000121 AC: 3 AN: 247212 Hom.: 0 AF XY: 0.0000149 AC XY: 2 AN XY: 134454

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000165

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: 0.00000342 AC: 5 AN: 1460862 Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3 AN XY: 726716

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000126

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

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 28, 2023

The c.64C>T (p.R22W) alteration is located in exon 1 (coding exon 1) of the SLC25A32 gene. This alteration results from a C to T substitution at nucleotide position 64, causing the arginine (R) at amino acid position 22 to be replaced by a tryptophan (W). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 15, 2023

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt SLC25A32 protein function. ClinVar contains an entry for this variant (Variation ID: 2461553). This variant has not been reported in the literature in individuals affected with SLC25A32-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.02%). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 22 of the SLC25A32 protein (p.Arg22Trp). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.36
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.050
CADD	Pathogenic	34
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.38	T
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.97	D
M_CAP	Uncertain	0.27	D
MetaRNN	Pathogenic	0.85	D
MetaSVM	Uncertain	-0.26	T
MutationAssessor	Uncertain	2.0	M
PrimateAI	Uncertain	0.62	T
PROVEAN	Pathogenic	-5.1	D
REVEL	Uncertain	0.45
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.59
MutPred		0.65		Loss of solvent accessibility (P = 0.0299);
MVP		0.96
MPC		1.0
ClinPred		1.0	D
GERP RS		5.0
Varity_R		0.76
gMVP		0.65

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: rs1440736635; hg19: chr8-104427102;