12-98593982-T-C

Position:

• chr12-98593982-T-C

Variant summary

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

The NM_002635.4(SLC25A3):​c.4T>C​(p.Phe2Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000682 in 1,613,818 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: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000068 (0 hom.)
• Consequence: SLC25A3 NM_002635.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.41

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=0.3799272).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC25A3	NM_005888.4	c.4T>C	p.Phe2Leu	missense_variant	2/8	ENST00000228318.8	NP_005879.1
SLC25A3	NM_002635.4	c.4T>C	p.Phe2Leu	missense_variant	2/8	ENST00000552981.6	NP_002626.1
SLC25A3	NM_213611.3	c.4T>C	p.Phe2Leu	missense_variant	1/7		NP_998776.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC25A3	ENST00000228318.8	c.4T>C	p.Phe2Leu	missense_variant	2/8	5	NM_005888.4	ENSP00000228318.3
SLC25A3	ENST00000552981.6	c.4T>C	p.Phe2Leu	missense_variant	2/8	1	NM_002635.4	ENSP00000448708.2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152180 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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000684 AC: 10 AN: 1461638 Hom.: 0 Cov.: 31 AF XY: 0.00000825 AC XY: 6 AN XY: 727152

Gnomad4 AFR exome AF: 0.00

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: 0.00

Gnomad4 NFE exome AF: 0.00000899

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152180 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74348

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: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Cardiomyopathy-hypotonia-lactic acidosis syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.61
BayesDel_addAF	Uncertain	0.092	D
BayesDel_noAF	Benign	-0.11
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.27	.;.;T;T;.;.;T;T;T;.;T
Eigen	Benign	-0.19
Eigen_PC	Benign	-0.077
FATHMM_MKL	Benign	0.67	D
LIST_S2	Benign	0.84	.;.;T;.;T;.;T;T;T;T;T
M_CAP	Uncertain	0.096	D
MetaRNN	Benign	0.38	T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.26	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		0.91
MPC		0.51
ClinPred		0.60	D
GERP RS		3.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.23
gMVP		0.77

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

Other links and lift over

dbSNP: rs886049919; hg19: chr12-98987760;