21-34095791-C-A

Variant names:

• chr21-34095791-C-A
• rs1978938123
• NM_006933.7:c.593C>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_006933.7(SLC5A3):​c.593C>A​(p.Thr198Lys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SLC5A3 NM_006933.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.95
• Publications: 0 publications found

Genes affected

SLC5A3 (HGNC:11038): (solute carrier family 5 member 3) Enables potassium channel regulator activity and transmembrane transporter binding activity. Predicted to be involved in inositol metabolic process; monosaccharide transmembrane transport; and myo-inositol import across plasma membrane. Predicted to act upstream of or within several processes, including peripheral nervous system development; positive regulation of reactive oxygen species biosynthetic process; and regulation of respiratory gaseous exchange. Located in plasma membrane. Part of perinuclear region of cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ENSG00000293606 (HGNC:):

MRPS6 (HGNC:14051): (mitochondrial ribosomal protein S6) Mammalian mitochondrial ribosomal proteins are encoded by nuclear genes and help in protein synthesis within the mitochondrion. Mitochondrial ribosomes (mitoribosomes) consist of a small 28S subunit and a large 39S subunit. They have an estimated 75% protein to rRNA composition compared to prokaryotic ribosomes, where this ratio is reversed. Another difference between mammalian mitoribosomes and prokaryotic ribosomes is that the latter contain a 5S rRNA. Among different species, the proteins comprising the mitoribosome differ greatly in sequence, and sometimes in biochemical properties, which prevents easy recognition by sequence homology. This gene encodes a 28S subunit protein that belongs to the ribosomal protein S6P family. Pseudogenes corresponding to this gene are found on chromosomes 1p and 12q. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.838

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC5A3	NM_006933.7	c.593C>A	p.Thr198Lys	missense_variant	Exon 2 of 2	ENST00000381151.5	NP_008864.4
MRPS6	NM_032476.4	c.45+22046C>A		intron_variant	Intron 1 of 2	ENST00000399312.3	NP_115865.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC5A3	ENST00000381151.5	c.593C>A	p.Thr198Lys	missense_variant	Exon 2 of 2	1	NM_006933.7	ENSP00000370543.3
ENSG00000293606	ENST00000715811.1	c.593C>A	p.Thr198Lys	missense_variant	Exon 2 of 4			ENSP00000520523.1
MRPS6	ENST00000399312.3	c.45+22046C>A		intron_variant	Intron 1 of 2	1	NM_032476.4	ENSP00000382250.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 02, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.593C>A (p.T198K) alteration is located in exon 2 (coding exon 1) of the SLC5A3 gene. This alteration results from a C to A substitution at nucleotide position 593, causing the threonine (T) at amino acid position 198 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.83
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.31
CADD	Uncertain	24
DANN	Uncertain	0.99
Eigen	Pathogenic	0.71
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Uncertain	0.24	D
MetaRNN	Pathogenic	0.84	D
MetaSVM	Uncertain	0.66	D
PhyloP100		5.0
PrimateAI	Uncertain	0.66	T
PROVEAN	Uncertain	-2.8	D
REVEL	Pathogenic	0.76
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.015	D
Vest4		0.73
MutPred		0.63		Gain of ubiquitination at T198 (P = 0.0219);
MVP		0.72
MPC		1.3
ClinPred		0.97	D
GERP RS		5.7
gMVP		0.96
Mutation Taster		=45/55	disease causing

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: rs1978938123; hg19: chr21-35468090;