3-139346988-A-C

Variant names:

• chr3-139346988-A-C
• rs73866065
• NM_020191.4:c.283A>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_020191.4(MRPS22):​c.283A>C​(p.Ile95Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00406 in 1,614,190 control chromosomes in the GnomAD database, including 191 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I95V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.021 (89 hom., cov: 32)
  • Exomes 𝑓: 0.0023 (102 hom.)
• Consequence: MRPS22 NM_020191.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.359
• Publications: 6 publications found

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 Gene-Disease associations (from GenCC):

• mitochondrial disease

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• hypotonia with lactic acidemia and hyperammonemia

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, G2P
• 46 XX gonadal dysgenesis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• ovarian dysgenesis 7

  Inheritance: AR Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0015542805).
• BP6: Variant 3-139346988-A-C is Benign according to our data. Variant chr3-139346988-A-C is described in ClinVar as Benign. ClinVar VariationId is 138251.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0658 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020191.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MRPS22	NM_020191.4	MANE Select	c.283A>C	p.Ile95Leu	missense	Exon 2 of 8	NP_064576.1
	MRPS22	NM_001363893.1		c.280A>C	p.Ile94Leu	missense	Exon 2 of 8	NP_001350822.1
	MRPS22	NM_001363857.1		c.160A>C	p.Ile54Leu	missense	Exon 2 of 8	NP_001350786.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MRPS22	ENST00000680020.1	MANE Select	c.283A>C	p.Ile95Leu	missense	Exon 2 of 8	ENSP00000505414.1
	MRPS22	ENST00000495075.5	TSL:1	c.283A>C	p.Ile95Leu	missense	Exon 4 of 10	ENSP00000418008.1
	MRPS22	ENST00000310776.9	TSL:1	c.280A>C	p.Ile94Leu	missense	Exon 2 of 8	ENSP00000310785.5

Frequencies

GnomAD3 genomes AF: 0.0206 AC: 3139 AN: 152192 Hom.: 89 Cov.: 32

Gnomad AFR AF: 0.0680

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0166

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000500

Gnomad OTH AF: 0.0153

GnomAD2 exomes AF: 0.00541 AC: 1361 AN: 251450 AF XY: 0.00403

Gnomad AFR exome AF: 0.0677

Gnomad AMR exome AF: 0.00567

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000924

Gnomad NFE exome AF: 0.000369

Gnomad OTH exome AF: 0.00293

GnomAD4 exome AF: 0.00233 AC: 3405 AN: 1461880 Hom.: 102 Cov.: 31 AF XY: 0.00200 AC XY: 1457 AN XY: 727240

African (AFR) AF: 0.0722 AC: 2418 AN: 33480

American (AMR) AF: 0.00555 AC: 248 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.000116 AC: 10 AN: 86258

European-Finnish (FIN) AF: 0.000131 AC: 7 AN: 53420

Middle Eastern (MID) AF: 0.00295 AC: 17 AN: 5768

European-Non Finnish (NFE) AF: 0.000369 AC: 410 AN: 1112004

Other (OTH) AF: 0.00488 AC: 295 AN: 60396

GnomAD4 genome AF: 0.0206 AC: 3141 AN: 152310 Hom.: 89 Cov.: 32 AF XY: 0.0198 AC XY: 1474 AN XY: 74484

African (AFR) AF: 0.0679 AC: 2820 AN: 41550

American (AMR) AF: 0.0165 AC: 253 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4828

European-Finnish (FIN) AF: 0.0000941 AC: 1 AN: 10630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000500 AC: 34 AN: 68022

Other (OTH) AF: 0.0151 AC: 32 AN: 2114

Alfa AF: 0.00728 Hom.: 60

Bravo AF: 0.0233

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0670 AC: 295

ESP6500EA AF: 0.000581 AC: 5

ExAC AF: 0.00635 AC: 771

Asia WGS AF: 0.00375 AC: 13 AN: 3478

EpiCase AF: 0.000545

EpiControl AF: 0.000415

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	1	Hypotonia with lactic acidemia and hyperammonemia (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	0.010
DANN	Benign	0.71
DEOGEN2	Benign	0.19	T
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.084	N
LIST_S2	Benign	0.68	T
MetaRNN	Benign	0.0016	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.34	N
PhyloP100		-0.36
PrimateAI	Benign	0.27	T
PROVEAN	Benign	0.23	N
REVEL	Benign	0.22
Sift	Benign	0.46	T
Sift4G	Benign	0.37	T
Polyphen		0.0	B
Vest4		0.19
MutPred		0.26		Gain of glycosylation at T90 (P = 0.0202)
MVP		0.40
MPC		0.28
ClinPred		0.0060	T
GERP RS		-11
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.041
gMVP		0.22
Mutation Taster		=98/2	polymorphism (auto)

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

Other links and lift over

dbSNP: rs73866065; hg19: chr3-139065830;