ENST00000188376.9:c.-25C>T

Variant names:

• chr12-98593954-C-T
• rs375070289
• ENST00000188376.9:c.-25C>T

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS1

The ENST00000188376.9(SLC25A3):​c.-25C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000533 in 1,613,706 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 Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00030 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000027 (0 hom.)
• Consequence: SLC25A3 ENST00000188376.9 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.303
• Publications: 0 publications found

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]

SLC25A3 Gene-Disease associations (from GenCC):

• cardiomyopathy-hypotonia-lactic acidosis syndrome

  Inheritance: AR Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet, PanelApp Australia
• mitochondrial disease

  Inheritance: AR Classification: MODERATE Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BP6: Variant 12-98593954-C-T is Benign according to our data. Variant chr12-98593954-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 512668.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000302 (46/152284) while in subpopulation AFR AF = 0.00111 (46/41570). AF 95% confidence interval is 0.000852. There are 0 homozygotes in GnomAd4. There are 20 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000188376.9. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC25A3	NM_005888.4	MANE Plus Clinical	c.-4-21C>T		intron	N/A	NP_005879.1	Q00325-1
	SLC25A3	NM_002635.4	MANE Select	c.-4-21C>T		intron	N/A	NP_002626.1	A0A024RBE8
	SLC25A3	NM_213611.3		c.-25C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 7	NP_998776.1	Q00325-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC25A3	ENST00000188376.9	TSL:1	c.-25C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 7	ENSP00000188376.5	Q00325-2
	SLC25A3	ENST00000188376.9	TSL:1	c.-25C>T		5_prime_UTR	Exon 1 of 7	ENSP00000188376.5	Q00325-2
	SLC25A3	ENST00000228318.8	TSL:5 MANE Plus Clinical	c.-4-21C>T		intron	N/A	ENSP00000228318.3	Q00325-1

Frequencies

GnomAD3 genomes AF: 0.000302 AC: 46 AN: 152166 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00111

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000919 AC: 23 AN: 250252 AF XY: 0.0000369

Gnomad AFR exome AF: 0.00143

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000274 AC: 40 AN: 1461422 Hom.: 0 Cov.: 31 AF XY: 0.0000220 AC XY: 16 AN XY: 727024

African (AFR) AF: 0.00102 AC: 34 AN: 33462

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26122

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86190

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53270

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111820

Other (OTH) AF: 0.0000662 AC: 4 AN: 60380

GnomAD4 genome AF: 0.000302 AC: 46 AN: 152284 Hom.: 0 Cov.: 33 AF XY: 0.000269 AC XY: 20 AN XY: 74456

African (AFR) AF: 0.00111 AC: 46 AN: 41570

American (AMR) AF: 0.00 AC: 0 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5162

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68008

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.000142 Hom.: 0

Bravo AF: 0.000314

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	6.9
DANN	Benign	0.87
PhyloP100		-0.30
PromoterAI		-0.056	Neutral

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs375070289; hg19: chr12-98987732;