21-34073744-G-T

Variant names:

• chr21-34073744-G-T
• rs549847334
• NM_006933.7:c.-338G>T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_006933.7(SLC5A3):​c.-338G>T variant causes a 5 prime UTR premature start codon gain change. The variant allele was found at a frequency of 0.000624 in 1,525,636 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00029 (2 hom., cov: 30)
  • Exomes 𝑓: 0.00066 (11 hom.)
• Consequence: SLC5A3 NM_006933.7 5_prime_UTR_premature_start_codon_gain
• Scores: Splicing: ADA: 0.5742
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.84
• 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: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008112222).
• BS2: High Homozygotes in GnomAd4 at 2 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC5A3	NM_006933.7	c.-338G>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 2	ENST00000381151.5	NP_008864.4
SLC5A3	NM_006933.7	c.-338G>T		splice_region_variant	Exon 1 of 2	ENST00000381151.5	NP_008864.4
MRPS6	NM_032476.4	c.44G>T	p.Arg15Leu	missense_variant, splice_region_variant	Exon 1 of 3	ENST00000399312.3	NP_115865.1
SLC5A3	NM_006933.7	c.-338G>T		5_prime_UTR_variant	Exon 1 of 2	ENST00000381151.5	NP_008864.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC5A3	ENST00000381151.5	c.-338G>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 2	1	NM_006933.7	ENSP00000370543.3
ENSG00000293606	ENST00000715811.1	c.-338G>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 4			ENSP00000520523.1
SLC5A3	ENST00000381151.5	c.-338G>T		splice_region_variant	Exon 1 of 2	1	NM_006933.7	ENSP00000370543.3
MRPS6	ENST00000399312.3	c.44G>T	p.Arg15Leu	missense_variant, splice_region_variant	Exon 1 of 3	1	NM_032476.4	ENSP00000382250.2
ENSG00000293606	ENST00000715811.1	c.-338G>T		splice_region_variant	Exon 1 of 4			ENSP00000520523.1
SLC5A3	ENST00000381151.5	c.-338G>T		5_prime_UTR_variant	Exon 1 of 2	1	NM_006933.7	ENSP00000370543.3
ENSG00000293606	ENST00000715811.1	c.-338G>T		5_prime_UTR_variant	Exon 1 of 4			ENSP00000520523.1

Frequencies

GnomAD3 genomes AF: 0.000275 AC: 41 AN: 149066 Hom.: 2 Cov.: 30

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000667

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00807

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000149

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00133 AC: 262 AN: 197700 AF XY: 0.00185

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000352

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000113

Gnomad OTH exome AF: 0.000219

GnomAD4 exome AF: 0.000660 AC: 908 AN: 1376462 Hom.: 11 Cov.: 30 AF XY: 0.000969 AC XY: 664 AN XY: 684980

African (AFR) AF: 0.00 AC: 0 AN: 27940

American (AMR) AF: 0.0000520 AC: 2 AN: 38498

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22932

East Asian (EAS) AF: 0.00 AC: 0 AN: 32388

South Asian (SAS) AF: 0.0102 AC: 829 AN: 81202

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48984

Middle Eastern (MID) AF: 0.000216 AC: 1 AN: 4630

European-Non Finnish (NFE) AF: 0.0000460 AC: 49 AN: 1064784

Other (OTH) AF: 0.000490 AC: 27 AN: 55104

GnomAD4 genome AF: 0.000295 AC: 44 AN: 149174 Hom.: 2 Cov.: 30 AF XY: 0.000467 AC XY: 34 AN XY: 72842

African (AFR) AF: 0.00 AC: 0 AN: 41292

American (AMR) AF: 0.0000666 AC: 1 AN: 15022

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3420

East Asian (EAS) AF: 0.00 AC: 0 AN: 5094

South Asian (SAS) AF: 0.00870 AC: 42 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9262

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.0000149 AC: 1 AN: 66976

Other (OTH) AF: 0.00 AC: 0 AN: 2078

Alfa AF: 0.000142 Hom.: 1

Bravo AF: 0.0000680

ExAC AF: 0.00127 AC: 153

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.67
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.11
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.12	T
Eigen	Uncertain	0.19
Eigen_PC	Benign	0.16
FATHMM_MKL	Benign	0.58	D
LIST_S2	Benign	0.77	T
MetaRNN	Benign	0.0081	T
MetaSVM	Benign	-0.79	T
MutationAssessor	Pathogenic	3.1	M
PhyloP100		4.8
PrimateAI	Uncertain	0.76	T
PROVEAN	Pathogenic	-4.6	D
REVEL	Benign	0.18
Sift	Uncertain	0.0060	D
Sift4G	Uncertain	0.0080	D
Polyphen		0.85	P
Vest4		0.52
MutPred		0.45		Loss of MoRF binding (P = 0.0083);
MVP		0.38
MPC		0.16
ClinPred		0.25	T
GERP RS		2.9
PromoterAI		-0.029	Neutral
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		3.8
Varity_R		0.40
gMVP		0.57
Mutation Taster		=79/21	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.57
dbscSNV1_RF	Benign	0.47
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: rs549847334; hg19: chr21-35446044; COSMIC: COSV100758018;