21-34073744-G-A

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_032476.4(MRPS6):c.44G>A(p.Arg15Gln) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000218 in 1,376,470 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 30)

Exomes 𝑓: 0.0000022 ( 0 hom. )

Consequence

MRPS6
NM_032476.4 missense, splice_region

Scores

Splicing: ADA: 0.1937

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.84

Variant links:

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]

SLC5A3 links:

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 links:

ENSG00000293606 (HGNC:):

ENSG00000293606 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.1556547).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC5A3	NM_006933.7 link	c.-338G>A		splice_region_variant	Exon 1 of 2	ENST00000381151.5	NP_008864.4
MRPS6	NM_032476.4 link	c.44G>A	p.Arg15Gln	missense_variant, splice_region_variant	Exon 1 of 3	ENST00000399312.3	NP_115865.1	P82932
SLC5A3	NM_006933.7 link	c.-338G>A		5_prime_UTR_variant	Exon 1 of 2	ENST00000381151.5	NP_008864.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SLC5A3	ENST00000381151.5 link	c.-338G>A		splice_region_variant	Exon 1 of 2	1	NM_006933.7	ENSP00000370543.3	P53794
MRPS6	ENST00000399312.3 link	c.44G>A	p.Arg15Gln	missense_variant, splice_region_variant	Exon 1 of 3	1	NM_032476.4	ENSP00000382250.2	P82932
ENSG00000293606	ENST00000715811.1 link	c.-338G>A		splice_region_variant	Exon 1 of 4			ENSP00000520523.1
SLC5A3	ENST00000381151.5 link	c.-338G>A		5_prime_UTR_variant	Exon 1 of 2	1	NM_006933.7	ENSP00000370543.3	P53794
ENSG00000293606	ENST00000715811.1 link	c.-338G>A		5_prime_UTR_variant	Exon 1 of 4			ENSP00000520523.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000506

AC:

AN:

197700

AF XY:

0.00000909

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

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:

0.00

GnomAD4 exome

AF:

0.00000218

AC:

AN:

1376470

Hom.:

Cov.:

AF XY:

0.00000292

AC XY:

AN XY:

684984

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

27940

American (AMR)

AF:

0.00

AC:

AN:

38498

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

22932

East Asian (EAS)

AF:

0.00

AC:

AN:

32388

South Asian (SAS)

AF:

0.00

AC:

AN:

81208

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48984

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4630

European-Non Finnish (NFE)

AF:

0.00000188

AC:

AN:

1064786

Other (OTH)

AF:

0.0000181

AC:

AN:

55104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.458

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ExAC

AF:

0.00000830

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 30, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.44G>A (p.R15Q) alteration is located in exon 1 (coding exon 1) of the MRPS6 gene. This alteration results from a G to A substitution at nucleotide position 44, causing the arginine (R) at amino acid position 15 to be replaced by a glutamine (Q). 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

0.38

BayesDel_addAF

Benign

-0.081

BayesDel_noAF

Benign

-0.35

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.078

Eigen

Benign

-0.29

Eigen_PC

Benign

-0.17

FATHMM_MKL

Benign

0.55

LIST_S2

Benign

0.70

M_CAP

Uncertain

0.22

MetaRNN

Benign

0.16

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.95

PhyloP100

4.8

PrimateAI

Uncertain

0.72

PROVEAN

Benign

-1.9

REVEL

Benign

0.20

Sift

Benign

0.26

Sift4G

Benign

0.28

Polyphen

0.064

Vest4

0.32

MutPred

0.37

Loss of MoRF binding (P = 0.0157);

MVP

0.17

MPC

0.045

ClinPred

0.43

GERP RS

2.9

PromoterAI

-0.079

Neutral

(source)

RBP_binding_hub_radar

0.92

RBP_regulation_power_radar

3.8

Varity_R

0.20

gMVP

0.48

Mutation Taster

=69/31

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.19

dbscSNV1_RF

Benign

0.34

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

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21-34073744-G-A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over