chr11-1952197-C-T

Variant names:

• chr11-1952197-C-T
• rs1223735915
• NM_021134.4:c.211C>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PP3

The NM_021134.4(MRPL23):​c.211C>T​(p.Arg71Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., cov: 1)
  • Exomes 𝑓: 0.000013 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: MRPL23 NM_021134.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.74
• Publications: 0 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: Uncertain_significance. The variant received 1 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.798

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MRPL23	NM_021134.4	c.211C>T	p.Arg71Trp	missense_variant	Exon 3 of 5	ENST00000397298.8	NP_066957.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MRPL23	ENST00000397298.8	c.211C>T	p.Arg71Trp	missense_variant	Exon 3 of 5	1	NM_021134.4	ENSP00000380466.3

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 7680 Hom.: 0 Cov.: 1

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: 0.00000798 AC: 2 AN: 250756 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000883

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000132 AC: 2 AN: 151550 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 79670

African (AFR) AF: 0.00 AC: 0 AN: 2540

American (AMR) AF: 0.00 AC: 0 AN: 4974

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 4590

East Asian (EAS) AF: 0.00 AC: 0 AN: 5794

South Asian (SAS) AF: 0.00 AC: 0 AN: 13590

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9912

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 638

European-Non Finnish (NFE) AF: 0.0000198 AC: 2 AN: 100832

Other (OTH) AF: 0.00 AC: 0 AN: 8680

GnomAD4 genome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 7680 Hom.: 0 Cov.: 1 AF XY: 0.00 AC XY: 0 AN XY: 3160

African (AFR) AF: 0.00 AC: 0 AN: 614

American (AMR) AF: 0.00 AC: 0 AN: 444

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 246

East Asian (EAS) AF: 0.00 AC: 0 AN: 120

South Asian (SAS) AF: 0.00 AC: 0 AN: 74

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 440

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 26

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 5572

Other (OTH) AF: 0.00 AC: 0 AN: 94

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 27, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.211C>T (p.R71W) alteration is located in exon 3 (coding exon 3) of the MRPL23 gene. This alteration results from a C to T substitution at nucleotide position 211, causing the arginine (R) at amino acid position 71 to be replaced by a tryptophan (W). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.50
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	0.060
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.032	T;T;T;T;T
Eigen	Uncertain	0.21
Eigen_PC	Benign	-0.0017
FATHMM_MKL	Benign	0.68	D
LIST_S2	Pathogenic	0.98	.;D;D;D;D
M_CAP	Benign	0.069	D
MetaRNN	Pathogenic	0.80	D;D;D;D;D
MetaSVM	Benign	-0.56	T
MutationAssessor	Uncertain	2.9	M;M;.;.;.
PhyloP100		1.7
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-6.7	D;D;D;D;D
REVEL	Uncertain	0.38
Sift	Uncertain	0.0010	D;D;D;D;D
Sift4G	Uncertain	0.0030	D;D;D;D;D
Polyphen		1.0	D;D;.;.;.
Vest4		0.84
MutPred		0.45		Loss of disorder (P = 0.0183);Loss of disorder (P = 0.0183);Loss of disorder (P = 0.0183);Loss of disorder (P = 0.0183);Loss of disorder (P = 0.0183);
MVP		0.61
MPC		0.70
ClinPred		0.97	D
GERP RS		1.7
Varity_R		0.90
gMVP		0.68
Mutation Taster		=50/50

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: rs1223735915; hg19: chr11-1973427;