17-81703536-C-T

Variant names:

• chr17-81703536-C-T
• rs777336686
• NM_002949.4:c.35C>T

Variant summary

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

The NM_002949.4(MRPL12):​c.35C>T​(p.Pro12Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000754 in 1,325,390 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 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. P12R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.5e-7 (0 hom.)
• Consequence: MRPL12 NM_002949.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.229
• Publications: 0 publications found

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]

MRPL12 Gene-Disease associations (from GenCC):

• combined oxidative phosphorylation deficiency 45

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

ENSG00000262660 (HGNC:):

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=0.11376545).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002949.4. 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
	MRPL12	NM_002949.4	MANE Select	c.35C>T	p.Pro12Leu	missense	Exon 1 of 5	NP_002940.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MRPL12	ENST00000333676.8	TSL:1 MANE Select	c.35C>T	p.Pro12Leu	missense	Exon 1 of 5	ENSP00000333837.3	P52815
	ENSG00000262660	ENST00000571730.1	TSL:2	c.35C>T	p.Pro12Leu	missense	Exon 1 of 15	ENSP00000461324.1	B4DLN1
	MRPL12	ENST00000853971.1		c.35C>T	p.Pro12Leu	missense	Exon 1 of 5	ENSP00000524030.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.54e-7 AC: 1 AN: 1325390 Hom.: 0 Cov.: 31 AF XY: 0.00000153 AC XY: 1 AN XY: 653016

African (AFR) AF: 0.00 AC: 0 AN: 26586

American (AMR) AF: 0.00 AC: 0 AN: 27914

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23054

East Asian (EAS) AF: 0.00 AC: 0 AN: 28870

South Asian (SAS) AF: 0.00 AC: 0 AN: 73538

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33556

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4404

European-Non Finnish (NFE) AF: 9.50e-7 AC: 1 AN: 1052616

Other (OTH) AF: 0.00 AC: 0 AN: 54852

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.021	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	14
DANN	Uncertain	0.99
DEOGEN2	Benign	0.030	T
Eigen	Benign	-0.68
Eigen_PC	Benign	-0.66
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.80	T
M_CAP	Uncertain	0.23	D
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-0.76	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		-0.23
PROVEAN	Benign	-0.85	N
REVEL	Benign	0.11
Sift	Benign	0.066	T
Sift4G	Benign	0.18	T
Polyphen		0.32	B
Vest4		0.14
MutPred		0.34		Loss of disorder (P = 0.0176)
MVP		0.72
MPC		0.21
ClinPred		0.67	D
GERP RS		4.0
PromoterAI		-0.13	Neutral
Varity_R		0.055
gMVP		0.38

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: rs777336686; hg19: chr17-79670566;