11-1950990-G-A

Variant names:

• chr11-1950990-G-A
• rs199601271
• NM_021134.4:c.109G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_021134.4(MRPL23):​c.109G>A​(p.Glu37Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 14/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00017 (0 hom., cov: 6)
  • Exomes 𝑓: 0.000086 (1 hom.)
  • Failed GnomAD Quality Control
• Consequence: MRPL23 NM_021134.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.22

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 -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.1342541).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MRPL23	NM_021134.4	c.109G>A	p.Glu37Lys	missense_variant	Exon 2 of 5	ENST00000397298.8	NP_066957.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MRPL23	ENST00000397298.8	c.109G>A	p.Glu37Lys	missense_variant	Exon 2 of 5	1	NM_021134.4	ENSP00000380466.3

Frequencies

GnomAD3 genomes AF: 0.000170 AC: 8 AN: 46966 Hom.: 0 Cov.: 6

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: 0.000563

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000256

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000107 AC: 25 AN: 233684 AF XY: 0.000103

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: 0.000549

Gnomad NFE exome AF: 0.000125

Gnomad OTH exome AF: 0.000172

GnomAD4 exome AF: 0.0000859 AC: 17 AN: 197978 Hom.: 1 Cov.: 0 AF XY: 0.0000978 AC XY: 10 AN XY: 102270

Gnomad4 AFR exome AF: 0.00 AC: 0 AN: 6460

Gnomad4 AMR exome AF: 0.00 AC: 0 AN: 4856

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 5298

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 14878

Gnomad4 SAS exome AF: 0.00 AC: 0 AN: 13364

Gnomad4 FIN exome AF: 0.000465 AC: 7 AN: 15062

Gnomad4 NFE exome AF: 0.0000558 AC: 7 AN: 125544

Gnomad4 Remaining exome AF: 0.000257 AC: 3 AN: 11664

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.000170 AC: 8 AN: 46966 Hom.: 0 Cov.: 6 AF XY: 0.0000928 AC XY: 2 AN XY: 21552

Gnomad4 AFR AF: 0.00 AC: 0 AN: 0

Gnomad4 AMR AF: 0.00 AC: 0 AN: 0

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.00 AC: 0 AN: 0

Gnomad4 FIN AF: 0.000563 AC: 0.00056338 AN: 0.00056338

Gnomad4 NFE AF: 0.000256 AC: 0.000255973 AN: 0.000255973

Gnomad4 OTH AF: 0.00 AC: 0 AN: 0

Alfa AF: 0.000352 Hom.: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000107 AC: 13

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 02, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.109G>A (p.E37K) alteration is located in exon 2 (coding exon 2) of the MRPL23 gene. This alteration results from a G to A substitution at nucleotide position 109, causing the glutamic acid (E) at amino acid position 37 to be replaced by a lysine (K). 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	Benign	0.11
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0022	T;T;T;T;T
Eigen	Benign	0.12
Eigen_PC	Benign	0.15
FATHMM_MKL	Benign	0.72	D
LIST_S2	Uncertain	0.94	.;D;D;D;D
M_CAP	Benign	0.0096	T
MetaRNN	Benign	0.13	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.1	L;L;.;.;.
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-0.61	N;N;N;N;N
REVEL	Benign	0.075
Sift	Benign	0.36	T;T;T;T;T
Sift4G	Benign	0.14	T;T;T;T;T
Polyphen		0.94	P;P;.;.;.
Vest4		0.53
MVP		0.48
MPC		0.25
ClinPred		0.11	T
GERP RS		4.5
Varity_R		0.36
gMVP		0.36
Mutation Taster		=92/8	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

Publications

LitVar

Other links and lift over

dbSNP: rs199601271; hg19: chr11-1972220; COSMIC: COSV67413689; COSMIC: COSV67413689;