3-139355793-A-G

Position:

• chr3-139355793-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_020191.4(MRPS22):​c.987+3A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000011 in 1,459,620 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: MRPS22 NM_020191.4 splice_region, intron
• Scores: Splicing: ADA: 0.9864
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.28

Genes affected

MRPS22 (HGNC:14508): (mitochondrial ribosomal protein S22) 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 does not seem to have a counterpart in prokaryotic and fungal-mitochondrial ribosomes. This gene lies telomeric of and is transcribed in the opposite direction from the forkhead box L2 gene. A pseudogene corresponding to this gene is found on chromosome Xq. [provided by RefSeq, Jul 2008]

MRPS22 (HGNC:):

COPB2 (HGNC:2232): (COPI coat complex subunit beta 2) The Golgi coatomer complex (see MIM 601924) constitutes the coat of nonclathrin-coated vesicles and is essential for Golgi budding and vesicular trafficking. It consists of 7 protein subunits, including COPB2.[supplied by OMIM, Jul 2002]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MRPS22	NM_020191.4	c.987+3A>G		splice_region_variant, intron_variant		ENST00000680020.1	NP_064576.1
MRPS22	NM_001363893.1	c.984+3A>G		splice_region_variant, intron_variant			NP_001350822.1
MRPS22	NM_001363857.1	c.864+3A>G		splice_region_variant, intron_variant			NP_001350786.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MRPS22	ENST00000680020.1	c.987+3A>G		splice_region_variant, intron_variant			NM_020191.4	ENSP00000505414.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000110 AC: 16 AN: 1459620 Hom.: 0 Cov.: 29 AF XY: 0.0000151 AC XY: 11 AN XY: 726304

Gnomad4 AFR exome AF: 0.00

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: 0.0000135

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 02, 2021

This sequence change falls in intron 7 of the MRPS22 gene. It does not directly change the encoded amino acid sequence of the MRPS22 protein. It affects a nucleotide within the consensus splice site. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with MRPS22-related conditions. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
CADD	Benign	20
DANN	Benign	0.85

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.99
dbscSNV1_RF	Pathogenic	0.80
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

No publications associated with this variant yet.

Other links and lift over

hg19: chr3-139074635;