rs142329098

Positions:

chr8-103403276-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3PP5

The NM_030780.5(SLC25A32):c.440G>A(p.Arg147His) variant causes a missense change. The variant allele was found at a frequency of 0.000171 in 1,612,240 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00020 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00017 ( 0 hom. )

Consequence

SLC25A32
NM_030780.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:2

Conservation

PhyloP100: 5.56

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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, 0.823

PP5

Variant 8-103403276-C-T is Pathogenic according to our data. Variant chr8-103403276-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 223106.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=2}. Variant chr8-103403276-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
SLC25A32	NM_030780.5 linkuse as main transcript	c.440G>A	p.Arg147His	missense_variant	4/7	ENST00000297578.9
SLC25A32	NR_102337.2 linkuse as main transcript	n.524G>A		non_coding_transcript_exon_variant	3/6
SLC25A32	NR_102338.2 linkuse as main transcript	n.719G>A		non_coding_transcript_exon_variant	5/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC25A32	ENST00000297578.9 linkuse as main transcript	c.440G>A	p.Arg147His	missense_variant	4/7	1	NM_030780.5	P1

Frequencies

GnomAD3 genomes

AF:

0.000204

AC:

AN:

151812

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000315

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:

0.00316

Gnomad NFE

AF:

0.000250

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000716

AC:

AN:

251262

Hom.:

AF XY:

0.0000589

AC XY:

AN XY:

135820

show subpopulations

Gnomad AFR exome

AF:

0.000369

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000880

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000168

AC:

245

AN:

1460314

Hom.:

Cov.:

AF XY:

0.000168

AC XY:

122

AN XY:

726560

show subpopulations

Gnomad4 AFR exome

AF:

0.000269

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.000207

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.000204

AC:

AN:

151926

Hom.:

Cov.:

AF XY:

0.000215

AC XY:

AN XY:

74264

show subpopulations

Gnomad4 AFR

AF:

0.000314

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:

0.000250

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000181

Hom.:

Bravo

AF:

0.000223

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.0000906

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Exercise intolerance, riboflavin-responsive

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Aug 24, 2021	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 12, 2020	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Dec 15, 2023

Variant summary: SLC25A32 c.440G>A (p.Arg147His) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 7.2e-05 in 251262 control chromosomes (gnomAD). c.440G>A has been reported in the literature in an individual affected with Exercise Intolerance, Riboflavin-Responsive who was compound heterozygous with a truncating variant (Schiff_2016). These data do not allow any conclusion about variant significance. This publication also reports experimental evidence evaluating an impact on protein function in a yeast model, finding that the missense variant in the orthologous protein results in significantly reduced enzymatic activity. The following publication has been ascertained in the context of this evaluation (PMID: 26933868). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, and classified it as pathogenic (n=1), likely pathogenic (n=1), or uncertain significance (n=1). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 21, 2024

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 147 of the SLC25A32 protein (p.Arg147His). This variant is present in population databases (rs142329098, gnomAD 0.04%). This missense change has been observed in individual(s) with recurrent exercise intolerance (PMID: 26933868). ClinVar contains an entry for this variant (Variation ID: 223106). 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 expected to disrupt SLC25A32 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects SLC25A32 function (PMID: 26933868). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.89

BayesDel_addAF

Pathogenic

0.23

BayesDel_noAF

Pathogenic

0.41

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.65

D;.

Eigen

Pathogenic

0.87

Eigen_PC

Pathogenic

0.77

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.97

D;D

M_CAP

Uncertain

0.11

MetaRNN

Pathogenic

0.82

D;D

MetaSVM

Pathogenic

0.96

MutationAssessor

Pathogenic

3.8

H;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.68

PROVEAN

Pathogenic

-4.9

D;.

REVEL

Pathogenic

0.89

Sift

Pathogenic

0.0

D;.

Sift4G

Pathogenic

0.0

D;.

Polyphen

1.0

D;.

Vest4

0.96

MVP

1.0

MPC

1.2

ClinPred

0.98

GERP RS

5.0

Varity_R

0.95

gMVP

0.91

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

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

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