12-98594014-C-A

Position:

• chr12-98594014-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_002635.4(SLC25A3):​c.36C>A​(p.Asn12Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,490 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: SLC25A3 NM_002635.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.73

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.4143163).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC25A3	NM_005888.4	c.36C>A	p.Asn12Lys	missense_variant	2/8	ENST00000228318.8	NP_005879.1
SLC25A3	NM_002635.4	c.36C>A	p.Asn12Lys	missense_variant	2/8	ENST00000552981.6	NP_002626.1
SLC25A3	NM_213611.3	c.36C>A	p.Asn12Lys	missense_variant	1/7		NP_998776.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC25A3	ENST00000228318.8	c.36C>A	p.Asn12Lys	missense_variant	2/8	5	NM_005888.4	ENSP00000228318.3
SLC25A3	ENST00000552981.6	c.36C>A	p.Asn12Lys	missense_variant	2/8	1	NM_002635.4	ENSP00000448708.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000120 AC: 3 AN: 250662 Hom.: 0 AF XY: 0.0000221 AC XY: 3 AN XY: 135730

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000579

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: 0.00000884

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461490 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727120

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000447

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000756

ExAC AF: 0.0000165 AC: 2

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

Labcorp Genetics (formerly Invitae), Labcorp

Apr 06, 2022

This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 12 of the SLC25A3 protein (p.Asn12Lys). This variant is present in population databases (rs747708858, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with SLC25A3-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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	0.65
BayesDel_addAF	Benign	-0.037	T
BayesDel_noAF	Benign	-0.11
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.34	.;.;T;T;.;.;T;T;T;.;T
Eigen	Uncertain	0.28
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Uncertain	0.97	.;.;D;.;D;.;D;D;D;D;D
M_CAP	Uncertain	0.16	D
MetaRNN	Benign	0.41	T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.48	D
MutationAssessor	Benign	0.69	N;N;N;N;.;N;.;.;.;N;.
PrimateAI	Uncertain	0.79	T
PROVEAN	Benign	-2.0	N;N;N;N;N;N;D;N;N;N;N
REVEL	Uncertain	0.39
Sift	Uncertain	0.0070	D;D;D;D;D;D;D;D;D;D;D
Sift4G	Benign	0.077	T;T;T;T;D;T;D;D;D;T;T
Polyphen		0.75	P;P;B;B;.;P;.;.;.;P;P
Vest4		0.78
MutPred		0.38		Gain of ubiquitination at N12 (P = 0.0408);Gain of ubiquitination at N12 (P = 0.0408);Gain of ubiquitination at N12 (P = 0.0408);Gain of ubiquitination at N12 (P = 0.0408);Gain of ubiquitination at N12 (P = 0.0408);Gain of ubiquitination at N12 (P = 0.0408);Gain of ubiquitination at N12 (P = 0.0408);Gain of ubiquitination at N12 (P = 0.0408);Gain of ubiquitination at N12 (P = 0.0408);Gain of ubiquitination at N12 (P = 0.0408);Gain of ubiquitination at N12 (P = 0.0408);
MVP		0.89
MPC		1.3
ClinPred		0.68	D
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.57
gMVP		0.88

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: rs747708858; hg19: chr12-98987792;