chr12-98598012-T-C

Variant names:

• chr12-98598012-T-C
• rs11544648
• NM_005888.4:c.439T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_002635.4(SLC25A3):​c.436T>C​(p.Leu146Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00594 in 1,613,580 control chromosomes in the GnomAD database, including 428 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.029 (210 hom., cov: 32)
  • Exomes 𝑓: 0.0035 (218 hom.)
• Consequence: SLC25A3 NM_002635.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.210
• Publications: 2 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BP6: Variant 12-98598012-T-C is Benign according to our data. Variant chr12-98598012-T-C is described in ClinVar as Benign. ClinVar VariationId is 139148.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.21 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0966 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002635.4. 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.439T>C	p.Leu147Leu	synonymous	Exon 4 of 8	NP_005879.1	Q00325-1
	SLC25A3	NM_002635.4	MANE Select	c.436T>C	p.Leu146Leu	synonymous	Exon 4 of 8	NP_002626.1	A0A024RBE8
	SLC25A3	NM_213611.3		c.436T>C	p.Leu146Leu	synonymous	Exon 3 of 7	NP_998776.1	Q00325-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC25A3	ENST00000228318.8	TSL:5 MANE Plus Clinical	c.439T>C	p.Leu147Leu	synonymous	Exon 4 of 8	ENSP00000228318.3	Q00325-1
	SLC25A3	ENST00000552981.6	TSL:1 MANE Select	c.436T>C	p.Leu146Leu	synonymous	Exon 4 of 8	ENSP00000448708.2	Q00325-2
	SLC25A3	ENST00000188376.9	TSL:1	c.436T>C	p.Leu146Leu	synonymous	Exon 3 of 7	ENSP00000188376.5	Q00325-2

Frequencies

GnomAD3 genomes AF: 0.0292 AC: 4450 AN: 152142 Hom.: 210 Cov.: 32

Gnomad AFR AF: 0.0993

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0124

Gnomad ASJ AF: 0.0101

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.000955

Gnomad OTH AF: 0.0192

GnomAD2 exomes AF: 0.00837 AC: 2104 AN: 251478 AF XY: 0.00628

Gnomad AFR exome AF: 0.103

Gnomad AMR exome AF: 0.00520

Gnomad ASJ exome AF: 0.0117

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000756

Gnomad OTH exome AF: 0.00635

GnomAD4 exome AF: 0.00351 AC: 5134 AN: 1461320 Hom.: 218 Cov.: 30 AF XY: 0.00314 AC XY: 2286 AN XY: 726998

African (AFR) AF: 0.104 AC: 3463 AN: 33448

American (AMR) AF: 0.00691 AC: 309 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00976 AC: 255 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.000209 AC: 18 AN: 86248

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00451 AC: 26 AN: 5768

European-Non Finnish (NFE) AF: 0.000553 AC: 615 AN: 1111518

Other (OTH) AF: 0.00742 AC: 448 AN: 60376

GnomAD4 genome AF: 0.0293 AC: 4454 AN: 152260 Hom.: 210 Cov.: 32 AF XY: 0.0280 AC XY: 2082 AN XY: 74460

African (AFR) AF: 0.0991 AC: 4117 AN: 41542

American (AMR) AF: 0.0124 AC: 190 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.0101 AC: 35 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.000956 AC: 65 AN: 68024

Other (OTH) AF: 0.0190 AC: 40 AN: 2108

Alfa AF: 0.0114 Hom.: 52

Bravo AF: 0.0337

Asia WGS AF: 0.00549 AC: 19 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	not specified (2)
-	-	1	Cardiomyopathy-hypotonia-lactic acidosis syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	9.2
DANN	Benign	0.63
PhyloP100		0.21
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

dbSNP: rs11544648; hg19: chr12-98991790;