16-1772946-C-G

Variant names:

• chr16-1772946-C-G
• rs1076695
• NM_023936.2:c.174G>C

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_023936.2(MRPS34):​c.174G>C​(p.Val58Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.124 in 1,445,350 control chromosomes in the GnomAD database, including 12,579 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.097 (997 hom., cov: 35)
  • Exomes 𝑓: 0.13 (11582 hom.)
• Consequence: MRPS34 NM_023936.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.73
• Publications: 10 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: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.34).
• BP6: Variant 16-1772946-C-G is Benign according to our data. Variant chr16-1772946-C-G is described in ClinVar as Benign. ClinVar VariationId is 1275184.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.73 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.137 is higher than 0.05.

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.174G>C	p.Val58Val	synonymous	Exon 1 of 3	NP_076425.1	P82930
	EME2	NM_001257370.2	MANE Select	c.-282C>G		5_prime_UTR	Exon 1 of 8	NP_001244299.1	A4GXA9-1
	MRPS34	NM_001300900.2		c.174G>C	p.Val58Val	synonymous	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.174G>C	p.Val58Val	synonymous	Exon 1 of 3	ENSP00000380531.3	P82930
	MRPS34	ENST00000177742.7	TSL:1	c.174G>C	p.Val58Val	synonymous	Exon 1 of 3	ENSP00000177742.3	C9JJ19
	EME2	ENST00000568449.7	TSL:1 MANE Select	c.-282C>G		5_prime_UTR	Exon 1 of 8	ENSP00000457353.1	A4GXA9-1

Frequencies

GnomAD3 genomes AF: 0.0967 AC: 14718 AN: 152206 Hom.: 997 Cov.: 35

Gnomad AFR AF: 0.0260

Gnomad AMI AF: 0.156

Gnomad AMR AF: 0.0996

Gnomad ASJ AF: 0.199

Gnomad EAS AF: 0.000770

Gnomad SAS AF: 0.0482

Gnomad FIN AF: 0.119

Gnomad MID AF: 0.232

Gnomad NFE AF: 0.139

Gnomad OTH AF: 0.111

GnomAD2 exomes AF: 0.0935 AC: 4511 AN: 48254 AF XY: 0.0939

Gnomad AFR exome AF: 0.0222

Gnomad AMR exome AF: 0.0782

Gnomad ASJ exome AF: 0.171

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.103

Gnomad NFE exome AF: 0.140

Gnomad OTH exome AF: 0.108

GnomAD4 exome AF: 0.127 AC: 164706 AN: 1293028 Hom.: 11582 Cov.: 67 AF XY: 0.126 AC XY: 79399 AN XY: 631970

African (AFR) AF: 0.0201 AC: 510 AN: 25364

American (AMR) AF: 0.0789 AC: 1539 AN: 19510

Ashkenazi Jewish (ASJ) AF: 0.180 AC: 3400 AN: 18856

East Asian (EAS) AF: 0.000190 AC: 6 AN: 31528

South Asian (SAS) AF: 0.0508 AC: 3295 AN: 64922

European-Finnish (FIN) AF: 0.115 AC: 4345 AN: 37762

Middle Eastern (MID) AF: 0.177 AC: 830 AN: 4700

European-Non Finnish (NFE) AF: 0.139 AC: 144267 AN: 1037018

Other (OTH) AF: 0.122 AC: 6514 AN: 53368

GnomAD4 genome AF: 0.0966 AC: 14708 AN: 152322 Hom.: 997 Cov.: 35 AF XY: 0.0940 AC XY: 7003 AN XY: 74478

African (AFR) AF: 0.0259 AC: 1076 AN: 41584

American (AMR) AF: 0.0995 AC: 1522 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.199 AC: 690 AN: 3470

East Asian (EAS) AF: 0.000772 AC: 4 AN: 5184

South Asian (SAS) AF: 0.0478 AC: 231 AN: 4832

European-Finnish (FIN) AF: 0.119 AC: 1266 AN: 10618

Middle Eastern (MID) AF: 0.233 AC: 68 AN: 292

European-Non Finnish (NFE) AF: 0.139 AC: 9477 AN: 68012

Other (OTH) AF: 0.110 AC: 232 AN: 2114

Alfa AF: 0.110 Hom.: 139

Bravo AF: 0.0933

Asia WGS AF: 0.0250 AC: 87 AN: 3470

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	MRPS34-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.34
CADD	Benign	14
DANN	Benign	0.91
PhyloP100		1.7
PromoterAI		0.033	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Mutation Taster		=100/0	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: rs1076695; hg19: chr16-1822947; COSMIC: COSV51602155; COSMIC: COSV51602155;