17-81704245-C-T

Variant names:

• chr17-81704245-C-T
• rs1214696093
• NM_002949.4:c.76C>T

Variant summary

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

The NM_002949.4(MRPL12):​c.76C>T​(p.Arg26*) variant causes a stop gained, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,452,014 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. R26R) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: MRPL12 NM_002949.4 stop_gained, splice_region
• Scores: Splicing: ADA: 0.9870
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.93
• 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.76C>T	p.Arg26*	stop_gained splice_region	Exon 2 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.76C>T	p.Arg26*	stop_gained splice_region	Exon 2 of 5	ENSP00000333837.3	P52815
	ENSG00000262660	ENST00000571730.1	TSL:2	c.76C>T	p.Arg26*	stop_gained splice_region	Exon 2 of 15	ENSP00000461324.1	B4DLN1
	MRPL12	ENST00000853971.1		c.76C>T	p.Arg26*	stop_gained splice_region	Exon 2 of 5	ENSP00000524030.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000414 AC: 1 AN: 241806 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1452014 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 722046

African (AFR) AF: 0.00 AC: 0 AN: 33170

American (AMR) AF: 0.00 AC: 0 AN: 43348

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25642

East Asian (EAS) AF: 0.00 AC: 0 AN: 39592

South Asian (SAS) AF: 0.0000117 AC: 1 AN: 85270

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52724

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4340

European-Non Finnish (NFE) AF: 9.02e-7 AC: 1 AN: 1108048

Other (OTH) AF: 0.00 AC: 0 AN: 59880

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	42
DANN	Uncertain	1.0
Eigen	Uncertain	0.68
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Benign	0.76	D
PhyloP100		2.9
Vest4		0.14
GERP RS		5.1
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.1
Mutation Taster		=31/169	disease causing (fs/PTC)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.99
SpliceAI score (max)		0.090		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: rs1214696093; hg19: chr17-79671275;