17-81704272-C-G

Position:

• chr17-81704272-C-G

Variant summary

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

The NM_002949.4(MRPL12):​c.103C>G​(p.Arg35Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,660 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. R35R) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: MRPL12 NM_002949.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0710

Genes affected

MRPL12 (HGNC:10378): (mitochondrial ribosomal protein L12) 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 39S subunit protein which forms homodimers. In prokaryotic ribosomes, two L7/L12 dimers and one L10 protein form the L8 protein complex. [provided by RefSeq, Jul 2008]

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	UniProt
MRPL12	NM_002949.4	c.103C>G	p.Arg35Gly	missense_variant	2/5	ENST00000333676.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MRPL12	ENST00000333676.8	c.103C>G	p.Arg35Gly	missense_variant	2/5	1	NM_002949.4	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459660 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726114

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: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 07, 2021

The c.103C>G (p.R35G) alteration is located in exon 2 (coding exon 2) of the MRPL12 gene. This alteration results from a C to G substitution at nucleotide position 103, causing the arginine (R) at amino acid position 35 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Uncertain	0.081	D
BayesDel_noAF	Benign	-0.12
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.16	T;.
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.43
FATHMM_MKL	Benign	0.21	N
LIST_S2	Benign	0.78	T;T
M_CAP	Uncertain	0.17	D
MetaRNN	Uncertain	0.69	D;D
MetaSVM	Uncertain	-0.16	T
MutationAssessor	Pathogenic	3.1	M;.
MutationTaster	Benign	1.0	N;N
PROVEAN	Uncertain	-3.6	D;.
REVEL	Uncertain	0.36
Sift	Uncertain	0.0050	D;.
Sift4G	Uncertain	0.0070	D;D
Polyphen		1.0	D;.
Vest4		0.85
MutPred		0.37		Loss of MoRF binding (P = 0.0139);Loss of MoRF binding (P = 0.0139);
MVP		0.95
MPC		0.90
ClinPred		0.98	D
GERP RS		0.80
Varity_R		0.33
gMVP		0.74

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

Publications

LitVar

Other links and lift over

dbSNP: rs1203865166; hg19: chr17-79671302;