chr21-34095304-G-A

Position:

• chr21-34095304-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The ENST00000381151.5(SLC5A3):​c.106G>A​(p.Val36Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000123 in 1,461,834 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: SLC5A3 ENST00000381151.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.72

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]

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]

MRPS6 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.763

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC5A3	NM_006933.7	c.106G>A	p.Val36Met	missense_variant	2/2	ENST00000381151.5	NP_008864.4
MRPS6	NM_032476.4	c.45+21559G>A		intron_variant		ENST00000399312.3	NP_115865.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC5A3	ENST00000381151.5	c.106G>A	p.Val36Met	missense_variant	2/2	1	NM_006933.7	ENSP00000370543.3
MRPS6	ENST00000399312.3	c.45+21559G>A		intron_variant		1	NM_032476.4	ENSP00000382250.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.0000119 AC: 3 AN: 251340 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135832

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000123 AC: 18 AN: 1461834 Hom.: 0 Cov.: 36 AF XY: 0.0000124 AC XY: 9 AN XY: 727220

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000153

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 26, 2022

The c.106G>A (p.V36M) alteration is located in exon 2 (coding exon 1) of the SLC5A3 gene. This alteration results from a G to A substitution at nucleotide position 106, causing the valine (V) at amino acid position 36 to be replaced by a methionine (M). 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	Uncertain	0.52
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	0.070
CADD	Pathogenic	28
DANN	Uncertain	1.0
Eigen	Pathogenic	0.99
Eigen_PC	Pathogenic	0.98
FATHMM_MKL	Pathogenic	0.97	D
M_CAP	Pathogenic	0.38	D
MetaRNN	Pathogenic	0.76	D
MetaSVM	Uncertain	0.71	D
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.87	D
PROVEAN	Uncertain	-2.5	D
REVEL	Uncertain	0.54
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.031	D
Vest4		0.62
MVP		0.94
MPC		1.2
ClinPred		0.96	D
GERP RS		6.1
gMVP		0.73

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

Publications

LitVar

Other links and lift over

dbSNP: rs143443984; hg19: chr21-35467603;