rs563189672

chr16-1772656-C-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2 PP5_Very_Strong

The NM_023936.2(MRPS34):c.322-10G>A variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000212 in 1,604,034 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.00015 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000076 (0 hom.)
• Consequence: MRPS34 NM_023936.2 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.9171
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 1.42

Genes affected

MRPS34 (HGNC:16618): (mitochondrial ribosomal protein S34) 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. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2014]

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 16-1772656-C-T is Pathogenic according to our data. Variant chr16-1772656-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 438633.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-1772656-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MRPS34	NM_023936.2	c.322-10G>A		splice_polypyrimidine_tract_variant, intron_variant		ENST00000397375.7
MRPS34	NM_001300900.2	c.322-10G>A		splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MRPS34	ENST00000397375.7	c.322-10G>A		splice_polypyrimidine_tract_variant, intron_variant		1	NM_023936.2	P1
MRPS34	ENST00000177742.7	c.322-10G>A		splice_polypyrimidine_tract_variant, intron_variant		1
MRPS34	ENST00000569585.1	n.43G>A		non_coding_transcript_exon_variant	1/2	2

Frequencies

GnomAD3 genomes AF: 0.000151 AC: 23 AN: 152266 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00131

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: 0.00

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.00000836 AC: 2 AN: 239276 Hom.: 0 AF XY: 0.00000761 AC XY: 1 AN XY: 131324

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000291

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: 0.000168

GnomAD4 exome AF: 0.00000758 AC: 11 AN: 1451650 Hom.: 0 Cov.: 32 AF XY: 0.00000554 AC XY: 4 AN XY: 722530

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000179

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: 0.00

Gnomad4 OTH exome AF: 0.0000498

GnomAD4 genome AF: 0.000151 AC: 23 AN: 152384 Hom.: 0 Cov.: 33 AF XY: 0.000148 AC XY: 11 AN XY: 74518

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00142

Bravo AF: 0.000374

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Combined oxidative phosphorylation deficiency 32 Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 28, 2023	Variant summary: MRPS34 c.322-10G>A alters a non-conserved nucleotide located at a position not widely known to affect splicing. Several computational tools predict a significant impact on normal splicing: Two predict the variant abolishes the 3' canonical acceptor site. One predict the variant weakens the 3' canonical acceptor site. Four predict the variant creates a 3' cryptic acceptor site. At least one publication reports experimental evidence that this variant affects mRNA splicing by producing abnormal transcripts that result in frameshift and premature truncation, respectively (Lake_2017). The variant allele was found at a frequency of 8.4e-06 in 239276 control chromosomes. c.322-10G>A has been reported at a homozygous state in multiple individuals affected with Leigh Syndrome (examples, MartinSaavedra_2021, Alves_2020, Lake_2017). These data indicate that the variant is very likely to be associated with Combined Oxidative Phosphorylation Deficiency 32. The following publications have been ascertained in the context of this evaluation (PMID: 32445240, 28777931, 34052969). Five submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 15, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Sep 27, 2022	- -
Pathogenic, no assertion criteria provided	clinical testing	Undiagnosed Diseases Network, NIH	Oct 21, 2022	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Sep 16, 2022	For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 438633). This variant has been observed in individual(s) with combined oxidative phosphorylation deficiency (PMID: 28777931). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs563189672, gnomAD 0.006%). This sequence change falls in intron 1 of the MRPS34 gene. It does not directly change the encoded amino acid sequence of the MRPS34 protein. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 19, 2022	Published functional studies demonstrate abnormal splicing resulting in a frameshift and premature truncation with 75% reduction in transcript level (Lake et al., 2017); Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 28777931, 33314036, 30358850, 32445240) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
Cadd	Benign	16
Dann	Benign	0.75
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.92
dbscSNV1_RF	Pathogenic	0.96
SpliceAI score (max)		0.93		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.93		Position offset: -2
DS_AL_spliceai		0.73		Position offset: -10

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs563189672; hg19: chr16-1822657;