NM_022829.6:c.1637G>T

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_022829.6(SLC13A3):​c.1637G>T​(p.Arg546Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. 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: not found (cov: 32)
• Consequence: SLC13A3 NM_022829.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.98
• Publications: 0 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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>T	p.Arg546Leu	missense	Exon 13 of 13	NP_073740.2
	SLC13A3	NM_001011554.3		c.1496G>T	p.Arg499Leu	missense	Exon 14 of 14	NP_001011554.1
	SLC13A3	NM_001193339.2		c.1487G>T	p.Arg496Leu	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>T	p.Arg546Leu	missense	Exon 13 of 13	ENSP00000279027.4
	SLC13A3	ENST00000495082.5	TSL:1	c.1496G>T	p.Arg499Leu	missense	Exon 12 of 12	ENSP00000419621.1
	SLC13A3	ENST00000290317.9	TSL:5	c.1496G>T	p.Arg499Leu	missense	Exon 13 of 13	ENSP00000290317.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Uncertain	0.074	D
BayesDel_noAF	Benign	-0.13
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.23	T
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.023	T
MetaRNN	Uncertain	0.67	D
MetaSVM	Benign	-1.2	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		3.0
PrimateAI	Uncertain	0.49	T
PROVEAN	Pathogenic	-4.5	D
REVEL	Benign	0.27
Sift	Uncertain	0.0020	D
Sift4G	Benign	0.070	T
Polyphen		0.97	D
Vest4		0.59
MutPred		0.70		Loss of methylation at R546 (P = 0.0167)
MVP		0.58
MPC		1.0
ClinPred		1.0	D
GERP RS		4.5
Varity_R		0.38
gMVP		0.78
Mutation Taster		=65/35	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;