NM_002949.4:c.75-66T>C

Variant names:

• chr17-81704178-T-C
• rs35815547
• NM_002949.4:c.75-66T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002949.4(MRPL12):​c.75-66T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0657 in 1,507,612 control chromosomes in the GnomAD database, including 4,288 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.067 (412 hom., cov: 33)
  • Exomes 𝑓: 0.066 (3876 hom.)
• Consequence: MRPL12 NM_002949.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.97
• Publications: 4 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 17-81704178-T-C is Benign according to our data. Variant chr17-81704178-T-C is described in ClinVar as Benign. ClinVar VariationId is 676743.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.208 is higher than 0.05.

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.75-66T>C		intron	N/A	NP_002940.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MRPL12	ENST00000333676.8	TSL:1 MANE Select	c.75-66T>C		intron	N/A	ENSP00000333837.3	P52815
	ENSG00000262660	ENST00000571730.1	TSL:2	c.75-66T>C		intron	N/A	ENSP00000461324.1	B4DLN1
	MRPL12	ENST00000853971.1		c.75-66T>C		intron	N/A	ENSP00000524030.1

Frequencies

GnomAD3 genomes AF: 0.0674 AC: 10237 AN: 151972 Hom.: 412 Cov.: 33

Gnomad AFR AF: 0.0719

Gnomad AMI AF: 0.158

Gnomad AMR AF: 0.0562

Gnomad ASJ AF: 0.0239

Gnomad EAS AF: 0.218

Gnomad SAS AF: 0.0822

Gnomad FIN AF: 0.0536

Gnomad MID AF: 0.0854

Gnomad NFE AF: 0.0578

Gnomad OTH AF: 0.0599

GnomAD4 exome AF: 0.0655 AC: 88792 AN: 1355522 Hom.: 3876 AF XY: 0.0655 AC XY: 43687 AN XY: 666694

African (AFR) AF: 0.0702 AC: 2142 AN: 30518

American (AMR) AF: 0.0460 AC: 1540 AN: 33464

Ashkenazi Jewish (ASJ) AF: 0.0282 AC: 596 AN: 21148

East Asian (EAS) AF: 0.262 AC: 10013 AN: 38146

South Asian (SAS) AF: 0.0729 AC: 5349 AN: 73386

European-Finnish (FIN) AF: 0.0484 AC: 2321 AN: 47960

Middle Eastern (MID) AF: 0.0669 AC: 249 AN: 3720

European-Non Finnish (NFE) AF: 0.0598 AC: 62892 AN: 1051392

Other (OTH) AF: 0.0661 AC: 3690 AN: 55788

GnomAD4 genome AF: 0.0674 AC: 10245 AN: 152090 Hom.: 412 Cov.: 33 AF XY: 0.0675 AC XY: 5015 AN XY: 74348

African (AFR) AF: 0.0721 AC: 2991 AN: 41472

American (AMR) AF: 0.0562 AC: 859 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0239 AC: 83 AN: 3466

East Asian (EAS) AF: 0.218 AC: 1126 AN: 5158

South Asian (SAS) AF: 0.0821 AC: 396 AN: 4824

European-Finnish (FIN) AF: 0.0536 AC: 567 AN: 10582

Middle Eastern (MID) AF: 0.0782 AC: 23 AN: 294

European-Non Finnish (NFE) AF: 0.0578 AC: 3932 AN: 67978

Other (OTH) AF: 0.0588 AC: 124 AN: 2108

Alfa AF: 0.0596 Hom.: 346

Bravo AF: 0.0689

Asia WGS AF: 0.150 AC: 521 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	1.6
DANN	Benign	0.76
PhyloP100		-2.0
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: rs35815547; hg19: chr17-79671208; COSMIC: COSV61268993; COSMIC: COSV61268993;