rs11544648

Positions:

• chr12-98598012-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_005888.4(SLC25A3):​c.439T>C​(p.Leu147=) 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_005888.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.210

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 Benign. Variant got -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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC25A3	NM_005888.4	c.439T>C	p.Leu147=	synonymous_variant	4/8	ENST00000228318.8
SLC25A3	NM_002635.4	c.436T>C	p.Leu146=	synonymous_variant	4/8	ENST00000552981.6
SLC25A3	NM_213611.3	c.436T>C	p.Leu146=	synonymous_variant	3/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC25A3	ENST00000228318.8	c.439T>C	p.Leu147=	synonymous_variant	4/8	5	NM_005888.4	A1
SLC25A3	ENST00000552981.6	c.436T>C	p.Leu146=	synonymous_variant	4/8	1	NM_002635.4	P3

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

GnomAD3 exomes AF: 0.00837 AC: 2104 AN: 251478 Hom.: 80 AF XY: 0.00628 AC XY: 853 AN XY: 135910

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 SAS exome AF: 0.000327

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

Gnomad4 AFR exome AF: 0.104

Gnomad4 AMR exome AF: 0.00691

Gnomad4 ASJ exome AF: 0.00976

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000209

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000553

Gnomad4 OTH exome AF: 0.00742

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

Gnomad4 AFR AF: 0.0991

Gnomad4 AMR AF: 0.0124

Gnomad4 ASJ AF: 0.0101

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000956

Gnomad4 OTH AF: 0.0190

Alfa AF: 0.0123 Hom.: 51

Bravo AF: 0.0337

Asia WGS AF: 0.00549 AC: 19 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Sep 15, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 06, 2012	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Cardiomyopathy-hypotonia-lactic acidosis syndrome Benign:1

Benign, 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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	9.2
DANN	Benign	0.63
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

Publications

LitVar

Other links and lift over

dbSNP: rs11544648; hg19: chr12-98991790;