12-98594016-C-T

Position:

• chr12-98594016-C-T

Variant summary

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

The NM_002635.4(SLC25A3):​c.38C>T​(p.Pro13Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000031 in 1,613,760 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: SLC25A3 NM_002635.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.51

Genes affected

SLC25A3 (HGNC:10989): (solute carrier family 25 member 3) The protein encoded by this gene catalyzes the transport of phosphate into the mitochondrial matrix, either by proton cotransport or in exchange for hydroxyl ions. The protein contains three related segments arranged in tandem which are related to those found in other characterized members of the mitochondrial carrier family. Both the N-terminal and C-terminal regions of this protein protrude toward the cytosol. Multiple alternatively spliced transcript variants have been isolated. [provided by RefSeq, Jul 2008]

ACMG classification

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/exons	MANE	Protein	UniProt
SLC25A3	NM_005888.4	c.38C>T	p.Pro13Leu	missense_variant	2/8	ENST00000228318.8	NP_005879.1
SLC25A3	NM_002635.4	c.38C>T	p.Pro13Leu	missense_variant	2/8	ENST00000552981.6	NP_002626.1
SLC25A3	NM_213611.3	c.38C>T	p.Pro13Leu	missense_variant	1/7		NP_998776.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC25A3	ENST00000228318.8	c.38C>T	p.Pro13Leu	missense_variant	2/8	5	NM_005888.4	ENSP00000228318.3
SLC25A3	ENST00000552981.6	c.38C>T	p.Pro13Leu	missense_variant	2/8	1	NM_002635.4	ENSP00000448708.2

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152230 Hom.: 0 Cov.: 33

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: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000798 AC: 2 AN: 250660 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135734

Gnomad AFR exome AF: 0.0000618

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: 0.0000463

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461530 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727120

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: 0.0000188

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152230 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74376

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: 0.0000294

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Aug 02, 2016

The P13L variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The P13L variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The P13L variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is not conserved. In silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret P13L as a variant of uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Benign	0.0014	T
BayesDel_noAF	Uncertain	-0.050
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.55	.;.;D;D;.;.;T;T;T;.;T
Eigen	Uncertain	0.22
Eigen_PC	Benign	0.21
FATHMM_MKL	Benign	0.66	D
LIST_S2	Uncertain	0.96	.;.;D;.;D;.;D;D;D;D;D
M_CAP	Uncertain	0.22	D
MetaRNN	Uncertain	0.54	D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.32	D
MutationAssessor	Benign	0.69	N;N;N;N;.;N;.;.;.;N;.
PrimateAI	Uncertain	0.76	T
PROVEAN	Uncertain	-3.9	D;D;D;D;D;D;D;D;D;D;D
REVEL	Uncertain	0.54
Sift	Uncertain	0.025	D;D;D;D;D;D;D;D;D;D;D
Sift4G	Uncertain	0.046	D;D;D;D;D;D;D;D;D;D;D
Polyphen		0.97	D;D;B;B;.;D;.;.;.;D;P
Vest4		0.54
MutPred		0.43		Loss of disorder (P = 0.0362);Loss of disorder (P = 0.0362);Loss of disorder (P = 0.0362);Loss of disorder (P = 0.0362);Loss of disorder (P = 0.0362);Loss of disorder (P = 0.0362);Loss of disorder (P = 0.0362);Loss of disorder (P = 0.0362);Loss of disorder (P = 0.0362);Loss of disorder (P = 0.0362);Loss of disorder (P = 0.0362);
MVP		0.94
MPC		0.65
ClinPred		0.40	T
GERP RS		3.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.28
gMVP		0.86

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1331004642; hg19: chr12-98987794;