9-128106391-G-C

Position:

chr9-128106391-G-C

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 1P and 2B. PP5BP4BS2_Supporting

The NM_001330988.2(SLC25A25):c.1083G>C(p.Gln361His) variant causes a missense change. The variant allele was found at a frequency of 0.0027 in 1,613,820 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

Frequency

Genomes: 𝑓 0.0018 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0028 ( 4 hom. )

Consequence

SLC25A25
NM_001330988.2 missense

Scores

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 4.24

Variant links:

Genes affected

SLC25A25 (HGNC:20663): (solute carrier family 25 member 25) The protein encoded by this gene belongs to the family of calcium-binding mitochondrial carriers, with a characteristic mitochondrial carrier domain at the C-terminus. These proteins are found in the inner membranes of mitochondria, and function as transport proteins. They shuttle metabolites, nucleotides and cofactors through the mitochondrial membrane and thereby connect and/or regulate cytoplasm and matrix functions. This protein may function as an ATP-Mg/Pi carrier that mediates the transport of Mg-ATP in exchange for phosphate, and likely responsible for the net uptake or efflux of adenine nucleotides into or from the mitochondria. Alternatively spliced transcript variants encoding different isoforms with a common C-terminus but variable N-termini have been described for this gene. [provided by RefSeq, Jul 2012]

SLC25A25 links:

SLC25A25 (HGNC:):

SLC25A25 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -1 ACMG points.

PP5

Variant 9-128106391-G-C is Pathogenic according to our data. Variant chr9-128106391-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 981158.Status of the report is no_assertion_criteria_provided, 0 stars.

BP4

Computational evidence support a benign effect (MetaRNN=0.01536572). . Strength limited to SUPPORTING due to the PP5.

BS2

High Homozygotes in GnomAdExome4 at 4 geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC25A25	NM_001330988.2 linkuse as main transcript	c.1083G>C	p.Gln361His	missense_variant	9/11	ENST00000373069.10	NP_001317917.1	Q6KCM7-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC25A25	ENST00000373069.10 linkuse as main transcript	c.1083G>C	p.Gln361His	missense_variant	9/11	5	NM_001330988.2	ENSP00000362160.5		Q6KCM7-3

Frequencies

GnomAD3 genomes

AF:

0.00185

AC:

281

AN:

152202

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000434

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00555

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00291

Gnomad OTH

AF:

0.00143

GnomAD3 exomes

AF:

0.00226

AC:

566

AN:

250818

Hom.:

AF XY:

0.00220

AC XY:

298

AN XY:

135570

show subpopulations

Gnomad AFR exome

AF:

0.000431

Gnomad AMR exome

AF:

0.000260

Gnomad ASJ exome

AF:

0.0000996

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00745

Gnomad NFE exome

AF:

0.00327

Gnomad OTH exome

AF:

0.00294

GnomAD4 exome

AF:

0.00279

AC:

4071

AN:

1461500

Hom.:

Cov.:

AF XY:

0.00266

AC XY:

1937

AN XY:

727050

show subpopulations

Gnomad4 AFR exome

AF:

0.000448

Gnomad4 AMR exome

AF:

0.000313

Gnomad4 ASJ exome

AF:

0.000115

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00751

Gnomad4 NFE exome

AF:

0.00316

Gnomad4 OTH exome

AF:

0.00204

GnomAD4 genome

AF:

0.00184

AC:

281

AN:

152320

Hom.:

Cov.:

AF XY:

0.00156

AC XY:

116

AN XY:

74480

show subpopulations

Gnomad4 AFR

AF:

0.000433

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00555

Gnomad4 NFE

AF:

0.00291

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.00244

Hom.:

Bravo

AF:

0.00145

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.00234

AC:

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.00221

AC:

ExAC

AF:

0.00262

AC:

318

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00234

EpiControl

AF:

0.00273

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Nephrolithiasis

Pathogenic:1

Pathogenic, no assertion criteria provided

research

Genomic Medicine Lab, University of Southampton

Jan 01, 2020

DNA from three stone-formers in a Southampton family (UK) and two from an Italian family were analyzed independently by whole exome sequencing. Selected variants were genotyped across all available members of both pedigrees. Mutated and wild type SLC25A25 expressed in yeast mitochondria was purified and incorporated into liposomes. [14C]-ATP uptake was measured with and without added calcium. All five patients had a heterozygous dominant variant (rs140777921; c.1047 G>C, p. Gln349His; Reference Sequence NM_001006641.3) of SLC25A25 which encodes the calcium regulated mitochondrial ATP-Mg/Pi carrier 3 (APC3). Non-stone formers also carried the variant indicating incomplete penetrance. From modelling, the variant may abolish a conserved polar interaction causing structural instability. Transport activity was reduced to approximately 20% of the wild type. Calcium regulation was unaffected. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.85

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Uncertain

0.070

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.60

.;.;.;.;D

Eigen

Uncertain

0.33

Eigen_PC

Uncertain

0.43

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.97

D;D;D;D;D

M_CAP

Uncertain

0.12

MetaRNN

Benign

0.015

T;T;T;T;T

MetaSVM

Benign

-0.86

MutationAssessor

Benign

1.0

.;.;.;.;L

PrimateAI

Uncertain

0.72

PROVEAN

Pathogenic

-4.4

D;D;D;D;D

REVEL

Uncertain

0.57

Sift

Pathogenic

0.0

D;D;D;D;D

Sift4G

Uncertain

0.0020

D;D;D;D;D

Polyphen

1.0

D;.;D;D;D

Vest4

0.69

MutPred

0.53

.;.;.;.;Loss of MoRF binding (P = 0.1234);

MVP

0.39

MPC

1.5

ClinPred

0.052

GERP RS

5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.80

gMVP

0.79

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

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