1-151763403-A-C

Position:

• chr1-151763403-A-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_031420.4(MRPL9):​c.77T>G​(p.Val26Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000113 in 1,413,210 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: not found (cov: 33)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: MRPL9 NM_031420.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.222

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]

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]

(HGNC:):

ACMG classification

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=0.06328678).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MRPL9	NM_031420.4	c.77T>G	p.Val26Gly	missense_variant	1/7	ENST00000368830.8	NP_113608.1
OAZ3	NM_001134939.1	c.32+236A>C		intron_variant			NP_001128411.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MRPL9	ENST00000368830.8	c.77T>G	p.Val26Gly	missense_variant	1/7	1	NM_031420.4	ENSP00000357823	P1
	ENST00000512280.1	n.363T>G		non_coding_transcript_exon_variant	3/3	3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000117 AC: 2 AN: 170476 Hom.: 0 AF XY: 0.0000220 AC XY: 2 AN XY: 91114

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000754

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: 0.0000113 AC: 16 AN: 1413210 Hom.: 0 Cov.: 32 AF XY: 0.0000100 AC XY: 7 AN XY: 698644

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000529

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: 0.0000129

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.0000169 AC: 2

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

Dec 18, 2023

The c.77T>G (p.V26G) alteration is located in exon 1 (coding exon 1) of the MRPL9 gene. This alteration results from a T to G substitution at nucleotide position 77, causing the valine (V) at amino acid position 26 to be replaced by a glycine (G). 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	0.077
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	12
DANN	Benign	0.95
DEOGEN2	Benign	0.011	T;.
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.0083	N
LIST_S2	Benign	0.45	T;T
M_CAP	Benign	0.029	D
MetaRNN	Benign	0.063	T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.4	L;.
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Uncertain	0.62	T
PROVEAN	Uncertain	-2.8	D;D
REVEL	Benign	0.019
Sift	Uncertain	0.0020	D;D
Sift4G	Uncertain	0.010	D;D
Polyphen		0.14	B;.
Vest4		0.24
MutPred		0.42		Gain of sheet (P = 0.0061);Gain of sheet (P = 0.0061);
MVP		0.12
MPC		0.77
ClinPred		0.19	T
GERP RS		-1.8
Varity_R		0.23
gMVP		0.62

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: rs768370611; hg19: chr1-151735879;