11-1956383-C-A

Variant names:

• chr11-1956383-C-A
• rs140352683
• NM_021134.4:c.425C>A

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP4

The NM_021134.4(MRPL23):​c.425C>A​(p.Pro142Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 14/22 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. P142L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., cov: 17)
  • Exomes 𝑓: 8.3e-7 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: MRPL23 NM_021134.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.15
• Publications: 4 publications found

Genes affected

MRPL23 (HGNC:10322): (mitochondrial ribosomal protein L23) 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. The gene is biallelically expressed, despite its location within a region of imprinted genes on chromosome 11. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Likely_benign. The variant received -1 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.34767258).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_021134.4. 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
	MRPL23	NM_021134.4	MANE Select	c.425C>A	p.Pro142Gln	missense	Exon 5 of 5	NP_066957.3
	MRPL23	NM_001400172.1		c.290C>A	p.Pro97Gln	missense	Exon 5 of 5	NP_001387101.1
	MRPL23	NM_001400174.1		c.*160C>A		3_prime_UTR	Exon 6 of 6	NP_001387103.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MRPL23	ENST00000397298.8	TSL:1 MANE Select	c.425C>A	p.Pro142Gln	missense	Exon 5 of 5	ENSP00000380466.3	Q16540
	MRPL23	ENST00000924183.1		c.581C>A	p.Pro194Gln	missense	Exon 5 of 5	ENSP00000594242.1
	MRPL23	ENST00000869798.1		c.431C>A	p.Pro144Gln	missense	Exon 5 of 5	ENSP00000539857.1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 133342 Hom.: 0 Cov.: 17

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00 AC: 0 AN: 239252 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 Data not reliable, filtered out with message: AS_VQSR AF: 8.35e-7 AC: 1 AN: 1197746 Hom.: 0 Cov.: 23 AF XY: 0.00000168 AC XY: 1 AN XY: 595784

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 28946

American (AMR) AF: 0.00 AC: 0 AN: 24960

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20966

East Asian (EAS) AF: 0.00 AC: 0 AN: 33808

South Asian (SAS) AF: 0.0000160 AC: 1 AN: 62616

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 36850

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4892

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 934668

Other (OTH) AF: 0.00 AC: 0 AN: 50040

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 133342 Hom.: 0 Cov.: 17 AF XY: 0.00 AC XY: 0 AN XY: 63824

African (AFR) AF: 0.00 AC: 0 AN: 38746

American (AMR) AF: 0.00 AC: 0 AN: 12122

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2990

East Asian (EAS) AF: 0.00 AC: 0 AN: 4356

South Asian (SAS) AF: 0.00 AC: 0 AN: 3256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8646

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 274

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 60354

Other (OTH) AF: 0.00 AC: 0 AN: 1762

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	20
DANN	Benign	0.97
DEOGEN2	Benign	0.092	T
Eigen	Benign	-0.13
Eigen_PC	Benign	-0.27
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.85	D
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.35	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		2.1
PrimateAI	Benign	0.39	T
PROVEAN	Uncertain	-2.7	D
REVEL	Benign	0.13
Sift	Benign	0.15	T
Sift4G	Benign	0.11	T
Polyphen		0.99	D
Vest4		0.42
MutPred		0.17		Loss of catalytic residue at P142 (P = 0.049)
MVP		0.44
MPC		0.57
ClinPred		0.75	D
GERP RS		2.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.091
gMVP		0.38
Mutation Taster		=58/42	polymorphism

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: rs140352683; hg19: chr11-1977613;