dbSNP rs147014855: SLC25A32:p.Trp142* (chr8-103403291-C-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_030780.5(SLC25A32):c.425G>A(p.Trp142*) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000484 in 1,611,096 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 (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000052 ( 0 hom. )

Consequence

SLC25A32
NM_030780.5 stop_gained

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts P:1U:2

Conservation

PhyloP100: 7.26

Variant links:

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]

SLC25A32 links:

ENSG00000285982 (HGNC:):

ENSG00000285982 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC25A32	NM_030780.5 link	c.425G>A	p.Trp142*	stop_gained	Exon 4 of 7	ENST00000297578.9	NP_110407.2	Q9H2D1
SLC25A32	NR_102337.2 link	n.509G>A		non_coding_transcript_exon_variant	Exon 3 of 6
SLC25A32	NR_102338.2 link	n.704G>A		non_coding_transcript_exon_variant	Exon 5 of 8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC25A32	ENST00000297578.9 link	c.425G>A	p.Trp142*	stop_gained	Exon 4 of 7	1	NM_030780.5	ENSP00000297578.4		Q9H2D1
ENSG00000285982	ENST00000649416.1 link	c.272G>A	p.Trp91*	stop_gained	Exon 6 of 9			ENSP00000496817.1		A0A3B3IRK5

Frequencies

GnomAD3 genomes

AF:

0.0000133

AC:

AN:

150796

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000295

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000318

AC:

AN:

251224

Hom.:

AF XY:

0.0000368

AC XY:

AN XY:

135796

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

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:

0.0000616

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000520

AC:

AN:

1460300

Hom.:

Cov.:

AF XY:

0.0000564

AC XY:

AN XY:

726488

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000621

Gnomad4 OTH exome

AF:

0.0000995

GnomAD4 genome

AF:

0.0000133

AC:

AN:

150796

Hom.:

Cov.:

AF XY:

0.0000136

AC XY:

AN XY:

73482

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000295

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000393

Hom.:

Bravo

AF:

0.0000151

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Exercise intolerance, riboflavin-responsive

Pathogenic:1

Oct 12, 2020

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not specified

Uncertain:1

Feb 13, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: SLC25A32 c.425G>A (p.Trp142X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, however current evidence is not sufficient to establish loss of function as a mechanism for disease. The variant allele was found at a frequency of 3.2e-05 in 251224 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.425G>A has been reported in the literature in at least one compound heterozygous individual affected with Exercise Intolerance, Riboflavin-Responsive (e.g., Schiff_2016). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 26933868). ClinVar contains an entry for this variant (Variation ID: 223105). Based on the evidence outlined above, the variant was classified as uncertain significance. -

not provided

Uncertain:1

Aug 04, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. ClinVar contains an entry for this variant (Variation ID: 223105). This premature translational stop signal has been observed in individual(s) with recurrent exercise intolerance (PMID: 26933868). This variant is present in population databases (rs147014855, gnomAD 0.007%). This sequence change creates a premature translational stop signal (p.Trp142*) in the SLC25A32 gene. It is expected to result in an absent or disrupted protein product. However, the current clinical and genetic evidence is not sufficient to establish whether loss-of-function variants in SLC25A32 cause disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.50

BayesDel_noAF

Pathogenic

0.58

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Pathogenic

0.96

Eigen_PC

Pathogenic

0.87

FATHMM_MKL

Pathogenic

0.98

Vest4

0.40

GERP RS

5.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.20

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.20

Position offset: -2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over