chr12-98593984-C-A

Variant names:

• chr12-98593984-C-A
• rs778865084
• NM_005888.4:c.6C>A

Variant summary

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

The NM_002635.4(SLC25A3):​c.6C>A​(p.Phe2Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: SLC25A3 NM_002635.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.75

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=0.3570938).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC25A3	NM_005888.4	c.6C>A	p.Phe2Leu	missense_variant	Exon 2 of 8	ENST00000228318.8	NP_005879.1
SLC25A3	NM_002635.4	c.6C>A	p.Phe2Leu	missense_variant	Exon 2 of 8	ENST00000552981.6	NP_002626.1
SLC25A3	NM_213611.3	c.6C>A	p.Phe2Leu	missense_variant	Exon 1 of 7		NP_998776.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC25A3	ENST00000228318.8	c.6C>A	p.Phe2Leu	missense_variant	Exon 2 of 8	5	NM_005888.4	ENSP00000228318.3
SLC25A3	ENST00000552981.6	c.6C>A	p.Phe2Leu	missense_variant	Exon 2 of 8	1	NM_002635.4	ENSP00000448708.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.61
BayesDel_addAF	Uncertain	0.080	D
BayesDel_noAF	Benign	-0.12
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.27	.;.;T;T;.;.;T;T;T;.;T
Eigen	Benign	-0.20
Eigen_PC	Benign	-0.076
FATHMM_MKL	Benign	0.71	D
LIST_S2	Benign	0.84	.;.;T;.;T;.;T;T;T;T;T
M_CAP	Benign	0.081	D
MetaRNN	Benign	0.36	T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.065	T
MutationAssessor	Benign	0.55	N;N;N;N;.;N;.;.;.;N;.
PrimateAI	Pathogenic	0.80	T
PROVEAN	Benign	-1.8	N;N;N;N;N;N;D;N;N;N;N
REVEL	Uncertain	0.33
Sift	Benign	0.076	T;T;T;T;T;T;D;T;T;T;T
Sift4G	Benign	0.086	T;T;T;T;T;T;D;T;T;T;T
Polyphen		0.0010	B;B;B;B;.;B;.;.;.;B;B
Vest4		0.48
MutPred		0.20		Gain of disorder (P = 0.111);Gain of disorder (P = 0.111);Gain of disorder (P = 0.111);Gain of disorder (P = 0.111);Gain of disorder (P = 0.111);Gain of disorder (P = 0.111);Gain of disorder (P = 0.111);Gain of disorder (P = 0.111);Gain of disorder (P = 0.111);Gain of disorder (P = 0.111);Gain of disorder (P = 0.111);
MVP		0.90
MPC		0.51
ClinPred		0.62	D
GERP RS		3.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.22
gMVP		0.77

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

Other links and lift over

dbSNP: rs778865084; hg19: chr12-98987762;