chr12-98593671-C-T

Variant names:

• chr12-98593671-C-T
• rs532766014
• ENST00000188376.9:c.-308C>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.-308C>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 0.000653 in 476,622 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 0.00036 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00079 (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: -1.82
• 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=-0.79).
• BP6: Variant 12-98593671-C-T is Benign according to our data. Variant chr12-98593671-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 310793.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000361 (55/152364) while in subpopulation EAS AF = 0.0102 (53/5184). AF 95% confidence interval is 0.00803. There are 0 homozygotes in GnomAd4. There are 30 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.-74C>T		upstream_gene	N/A	NP_005879.1	Q00325-1
	SLC25A3	NM_002635.4	MANE Select	c.-74C>T		upstream_gene	N/A	NP_002626.1	A0A024RBE8
	SLC25A3	NM_213611.3		c.-308C>T		upstream_gene	N/A	NP_998776.1	Q00325-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC25A3	ENST00000188376.9	TSL:1	c.-308C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 7	ENSP00000188376.5	Q00325-2
	SLC25A3	ENST00000401722.7	TSL:1	c.-70C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 8	ENSP00000383898.3	Q00325-2
	SLC25A3	ENST00000188376.9	TSL:1	c.-308C>T		5_prime_UTR	Exon 1 of 7	ENSP00000188376.5	Q00325-2

Frequencies

GnomAD3 genomes AF: 0.000368 AC: 56 AN: 152246 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: 0.0104

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000956

GnomAD4 exome AF: 0.000789 AC: 256 AN: 324258 Hom.: 0 Cov.: 0 AF XY: 0.000767 AC XY: 131 AN XY: 170886

African (AFR) AF: 0.00 AC: 0 AN: 9672

American (AMR) AF: 0.0000674 AC: 1 AN: 14836

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 10064

East Asian (EAS) AF: 0.0123 AC: 243 AN: 19818

South Asian (SAS) AF: 0.00 AC: 0 AN: 42376

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 17354

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1352

European-Non Finnish (NFE) AF: 0.00000526 AC: 1 AN: 190190

Other (OTH) AF: 0.000592 AC: 11 AN: 18596

GnomAD4 genome AF: 0.000361 AC: 55 AN: 152364 Hom.: 0 Cov.: 33 AF XY: 0.000403 AC XY: 30 AN XY: 74504

African (AFR) AF: 0.00 AC: 0 AN: 41598

American (AMR) AF: 0.00 AC: 0 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.0102 AC: 53 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68026

Other (OTH) AF: 0.000946 AC: 2 AN: 2114

Alfa AF: 0.000208 Hom.: 0

Bravo AF: 0.000287

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Cardiomyopathy-hypotonia-lactic acidosis syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	0.32
DANN	Benign	0.87
PhyloP100		-1.8
PromoterAI		-0.30	Neutral

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

Other links and lift over

dbSNP: rs532766014; hg19: chr12-98987449; COSMIC: COSV51846361;