20-46560194-C-T

Variant names:

• chr20-46560194-C-T
• rs188700676
• NM_022829.6:c.1637G>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_022829.6(SLC13A3):​c.1637G>A​(p.Arg546Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000169 in 1,614,010 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R546W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00014 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00017 (0 hom.)
• Consequence: SLC13A3 NM_022829.6 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 2.98
• Publications: 8 publications found

Genes affected

SLC13A3 (HGNC:14430): (solute carrier family 13 member 3) Mammalian sodium-dicarboxylate cotransporters transport succinate and other Krebs cycle intermediates. They fall into 2 categories based on their substrate affinity: low affinity and high affinity. Both the low- and high-affinity transporters play an important role in the handling of citrate by the kidneys. The protein encoded by this gene represents the high-affinity form. Alternatively spliced transcript variants encoding different isoforms have been found for this gene, although the full-length nature of some of them have not been characterized yet. [provided by RefSeq, Jul 2008]

SLC13A3 Gene-Disease associations (from GenCC):

• leukoencephalopathy, acute reversible, with increased urinary alpha-ketoglutarate

  Inheritance: AR, Unknown Classification: LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Illumina

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.031536788).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_022829.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC13A3	NM_022829.6	MANE Select	c.1637G>A	p.Arg546Gln	missense	Exon 13 of 13	NP_073740.2
	SLC13A3	NM_001011554.3		c.1496G>A	p.Arg499Gln	missense	Exon 14 of 14	NP_001011554.1
	SLC13A3	NM_001193339.2		c.1487G>A	p.Arg496Gln	missense	Exon 12 of 12	NP_001180268.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC13A3	ENST00000279027.9	TSL:1 MANE Select	c.1637G>A	p.Arg546Gln	missense	Exon 13 of 13	ENSP00000279027.4
	SLC13A3	ENST00000495082.5	TSL:1	c.1496G>A	p.Arg499Gln	missense	Exon 12 of 12	ENSP00000419621.1
	SLC13A3	ENST00000290317.9	TSL:5	c.1496G>A	p.Arg499Gln	missense	Exon 13 of 13	ENSP00000290317.5

Frequencies

GnomAD3 genomes AF: 0.000145 AC: 22 AN: 152126 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00135

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000157 AC: 39 AN: 248184 AF XY: 0.000201

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000869

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00125

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000117

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000172 AC: 251 AN: 1461766 Hom.: 0 Cov.: 31 AF XY: 0.000172 AC XY: 125 AN XY: 727192

African (AFR) AF: 0.0000597 AC: 2 AN: 33476

American (AMR) AF: 0.000112 AC: 5 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

East Asian (EAS) AF: 0.000378 AC: 15 AN: 39698

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53402

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.000197 AC: 219 AN: 1111938

Other (OTH) AF: 0.000149 AC: 9 AN: 60388

GnomAD4 genome AF: 0.000145 AC: 22 AN: 152244 Hom.: 0 Cov.: 32 AF XY: 0.0000940 AC XY: 7 AN XY: 74440

African (AFR) AF: 0.0000241 AC: 1 AN: 41538

American (AMR) AF: 0.00 AC: 0 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00135 AC: 7 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4812

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

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

European-Non Finnish (NFE) AF: 0.000206 AC: 14 AN: 68016

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.000137 Hom.: 0

Bravo AF: 0.000189

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000140 AC: 17

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Leukoencephalopathy, acute reversible, with increased urinary alpha-ketoglutarate (1)
-	1	-	not provided (1)
-	1	-	Prostate cancer (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.20
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.15	T
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.81	T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.032	T
MetaSVM	Benign	-1.2	T
MutationAssessor	Pathogenic	3.2	M
PhyloP100		3.0
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.25
Sift	Benign	0.031	D
Sift4G	Uncertain	0.016	D
Polyphen		1.0	D
Vest4		0.47
MVP		0.51
MPC		0.94
ClinPred		0.36	T
GERP RS		4.5
Varity_R		0.10
gMVP		0.63
Mutation Taster		=85/15	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs188700676; hg19: chr20-45188833; COSMIC: COSV51713459;