17-81704124-G-A

Variant names:

• chr17-81704124-G-A
• rs145265749
• NM_002949.4:c.75-120G>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_002949.4(MRPL12):​c.75-120G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00206 in 1,016,154 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0022 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0020 (0 hom.)
• Consequence: MRPL12 NM_002949.4 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.643
• 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: Likely_benign. The variant received -4 ACMG points.

• PM2: Variant has high frequency in the NFE (0.00175) population. However there is too low homozygotes in high coverage region: (expected more than 1, got 0).
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 17-81704124-G-A is Benign according to our data. Variant chr17-81704124-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 1317977.Status of the report is criteria_provided_single_submitter, 1 stars.

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.75-120G>A		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.75-120G>A		intron	N/A	ENSP00000333837.3	P52815
	ENSG00000262660	ENST00000571730.1	TSL:2	c.75-120G>A		intron	N/A	ENSP00000461324.1	B4DLN1
	MRPL12	ENST00000853971.1		c.75-120G>A		intron	N/A	ENSP00000524030.1

Frequencies

GnomAD3 genomes AF: 0.00219 AC: 333 AN: 152190 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000290

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0151

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00222

Gnomad OTH AF: 0.00239

GnomAD4 exome AF: 0.00204 AC: 1765 AN: 863846 Hom.: 0 AF XY: 0.00193 AC XY: 834 AN XY: 432522

African (AFR) AF: 0.000200 AC: 4 AN: 20006

American (AMR) AF: 0.000284 AC: 5 AN: 17614

Ashkenazi Jewish (ASJ) AF: 0.0000624 AC: 1 AN: 16018

East Asian (EAS) AF: 0.00 AC: 0 AN: 31832

South Asian (SAS) AF: 0.00 AC: 0 AN: 52824

European-Finnish (FIN) AF: 0.0141 AC: 501 AN: 35564

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2748

European-Non Finnish (NFE) AF: 0.00183 AC: 1189 AN: 648090

Other (OTH) AF: 0.00166 AC: 65 AN: 39150

GnomAD4 genome AF: 0.00218 AC: 332 AN: 152308 Hom.: 0 Cov.: 33 AF XY: 0.00266 AC XY: 198 AN XY: 74464

African (AFR) AF: 0.000289 AC: 12 AN: 41558

American (AMR) AF: 0.000327 AC: 5 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.0151 AC: 160 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00221 AC: 150 AN: 68018

Other (OTH) AF: 0.00237 AC: 5 AN: 2110

Alfa AF: 0.00204 Hom.: 0

Bravo AF: 0.000858

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	3.8
DANN	Benign	0.55
PhyloP100		0.64
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs145265749; hg19: chr17-79671154;