1-151763445-G-A

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_031420.4(MRPL9):c.35C>T(p.Ala12Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000089 in 1,572,692 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000056 ( 0 hom. )

Consequence

MRPL9
NM_031420.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.284

Variant links:

Genes affected

MRPL9 (HGNC:14277): (mitochondrial ribosomal protein L9) This is a nuclear gene encoding a protein component of the 39S subunit of the mitochondrial ribosome. Alternative splicing results in multiple transcript variants. A pseudogene of this gene is found on chromosome 8. [provided by RefSeq, Jul 2014]

MRPL9 links:

OAZ3 (HGNC:8097): (ornithine decarboxylase antizyme 3) The protein encoded by this gene belongs to the ornithine decarboxylase antizyme family, which plays a role in cell growth and proliferation by regulating intracellular polyamine levels. Expression of antizymes requires +1 ribosomal frameshifting, which is enhanced by high levels of polyamines. Antizymes in turn bind to and inhibit ornithine decarboxylase (ODC), the key enzyme in polyamine biosynthesis; thus, completing the auto-regulatory circuit. This gene encodes antizyme 3, the third member of the antizyme family. Like antizymes 1 and 2, antizyme 3 inhibits ODC activity and polyamine uptake; however, it does not stimulate ODC degradation. Also, while antizymes 1 and 2 have broad tissue distribution, expression of antizyme 3 is restricted to haploid germ cells in testis, suggesting a distinct role for this antizyme in spermiogenesis. Antizyme 3 gene knockout studies showed that homozygous mutant male mice were infertile, and indicated the likely role of this antizyme in the formation of a rigid connection between the sperm head and tail during spermatogenesis. Alternatively spliced transcript variants encoding different isoforms, including one resulting from the use of non-AUG (CUG) translation initiation codon, have been found for this gene. [provided by RefSeq, Dec 2014]

OAZ3 links:

ENSG00000249602 (HGNC:):

ENSG00000249602 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.0639582).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MRPL9	NM_031420.4 link	c.35C>T	p.Ala12Val	missense_variant	Exon 1 of 7	ENST00000368830.8	NP_113608.1	Q9BYD2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
MRPL9	ENST00000368830.8 link	c.35C>T	p.Ala12Val	missense_variant	Exon 1 of 7	1	NM_031420.4	ENSP00000357823.3	Q9BYD2
OAZ3	ENST00000321531.10 link	c.32+278G>A		intron_variant	Intron 1 of 5	5		ENSP00000313922.5	A0A0G2JH29
OAZ3	ENST00000635322.1 link	c.32+278G>A		intron_variant	Intron 1 of 4	5		ENSP00000489350.1	A0A0U1RR57
OAZ3	ENST00000453029.2 link	c.-50G>A		upstream_gene_variant		5		ENSP00000415904.2	H0Y7Y4
OAZ3	ENST00000479764.7 link	c.-3277G>A		upstream_gene_variant		5		ENSP00000463055.3	Q5SZR7

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152232

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000167

AC:

AN:

179460

Hom.:

AF XY:

0.0000103

AC XY:

AN XY:

97186

show subpopulations

Gnomad AFR exome

AF:

0.000319

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000563

AC:

AN:

1420460

Hom.:

Cov.:

AF XY:

0.00000427

AC XY:

AN XY:

702914

show subpopulations

Gnomad4 AFR exome

AF:

0.000123

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000367

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152232

Hom.:

Cov.:

AF XY:

0.0000672

AC XY:

AN XY:

74364

show subpopulations

Gnomad4 AFR

AF:

0.000121

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000540

Hom.:

Bravo

AF:

0.0000151

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 07, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.35C>T (p.A12V) alteration is located in exon 1 (coding exon 1) of the MRPL9 gene. This alteration results from a C to T substitution at nucleotide position 35, causing the alanine (A) at amino acid position 12 to be replaced by a valine (V). 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

Benign

0.16

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.60

CADD

Benign

8.6

DANN

Uncertain

0.98

DEOGEN2

Benign

0.0036

T;.

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.0034

LIST_S2

Benign

0.76

T;T

M_CAP

Benign

0.0098

MetaRNN

Benign

0.064

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.5

L;.

PrimateAI

Uncertain

0.64

PROVEAN

Benign

-0.65

N;N

REVEL

Benign

0.095

Sift

Benign

0.20

T;T

Sift4G

Benign

0.21

T;T

Polyphen

0.0

B;.

Vest4

0.13

MutPred

0.34

Gain of sheet (P = 0.0061);Gain of sheet (P = 0.0061);

MVP

0.20

MPC

0.54

ClinPred

0.019

GERP RS

0.30

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.062

gMVP

0.51

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over