rs990190809

Variant names:

• chr16-1772974-C-A
• rs990190809
• NM_023936.2:c.146G>T

Your query was ambiguous. Multiple possible variants found:

• chr16-1772974-C-A
• chr16-1772974-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_023936.2(MRPS34):​c.146G>T​(p.Arg49Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000207 in 1,447,596 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R49Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 35)
  • Exomes 𝑓: 0.0000015 (0 hom.)
• Consequence: MRPS34 NM_023936.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.389
• Publications: 0 publications found

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]

EME2 (HGNC:27289): (essential meiotic structure-specific endonuclease subunit 2) EME2 forms a heterodimer with MUS81 (MIM 606591) that functions as an XPF (MIM 278760)-type flap/fork endonuclease in DNA repair (Ciccia et al., 2007 [PubMed 17289582]).[supplied by OMIM, Mar 2008]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.22504044).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_023936.2. 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
	MRPS34	NM_023936.2	MANE Select	c.146G>T	p.Arg49Leu	missense	Exon 1 of 3	NP_076425.1	P82930
	EME2	NM_001257370.2	MANE Select	c.-254C>A		5_prime_UTR	Exon 1 of 8	NP_001244299.1	A4GXA9-1
	MRPS34	NM_001300900.2		c.146G>T	p.Arg49Leu	missense	Exon 1 of 3	NP_001287829.1	C9JJ19

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MRPS34	ENST00000397375.7	TSL:1 MANE Select	c.146G>T	p.Arg49Leu	missense	Exon 1 of 3	ENSP00000380531.3	P82930
	MRPS34	ENST00000177742.7	TSL:1	c.146G>T	p.Arg49Leu	missense	Exon 1 of 3	ENSP00000177742.3	C9JJ19
	EME2	ENST00000568449.7	TSL:1 MANE Select	c.-254C>A		5_prime_UTR	Exon 1 of 8	ENSP00000457353.1	A4GXA9-1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152250 Hom.: 0 Cov.: 35

Gnomad AFR AF: 0.00

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

GnomAD4 exome AF: 0.00000154 AC: 2 AN: 1295346 Hom.: 0 Cov.: 63 AF XY: 0.00 AC XY: 0 AN XY: 633312

African (AFR) AF: 0.00 AC: 0 AN: 25246

American (AMR) AF: 0.00 AC: 0 AN: 20282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19388

East Asian (EAS) AF: 0.00 AC: 0 AN: 30732

South Asian (SAS) AF: 0.00 AC: 0 AN: 65810

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40736

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5048

European-Non Finnish (NFE) AF: 0.00000193 AC: 2 AN: 1034688

Other (OTH) AF: 0.00 AC: 0 AN: 53416

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152250 Hom.: 0 Cov.: 35 AF XY: 0.0000134 AC XY: 1 AN XY: 74382

African (AFR) AF: 0.00 AC: 0 AN: 41466

American (AMR) AF: 0.00 AC: 0 AN: 15286

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5206

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68044

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	18
DANN	Uncertain	0.98
DEOGEN2	Benign	0.070	T
Eigen	Benign	-0.64
Eigen_PC	Benign	-0.69
FATHMM_MKL	Benign	0.66	D
LIST_S2	Benign	0.78	T
M_CAP	Pathogenic	0.35	D
MetaRNN	Benign	0.23	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		0.39
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.052
Sift	Uncertain	0.022	D
Sift4G	Benign	0.075	T
Polyphen		0.51	P
Vest4		0.21
MutPred		0.40		Loss of methylation at R49 (P = 0.0216)
MVP		0.39
MPC		2.2
ClinPred		0.54	D
GERP RS		0.58
PromoterAI		-0.037	Neutral
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.7
Varity_R		0.079
gMVP		0.60

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: rs990190809; hg19: chr16-1822975;