2-223959821-T-G

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2PP3_ModeratePP5_Very_Strong

The NM_022915.5(MRPL44):​c.467T>G​(p.Leu156Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000338 in 1,614,086 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.00016 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00036 ( 0 hom. )

Consequence

MRPL44
NM_022915.5 missense

Scores

5
9
5

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6

Conservation

PhyloP100: 7.48
Variant links:
Genes affected
MRPL44 (HGNC:16650): (mitochondrial ribosomal protein L44) 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. [provided by RefSeq, Jul 2008]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.84
PP5
Variant 2-223959821-T-G is Pathogenic according to our data. Variant chr2-223959821-T-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 64624.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-223959821-T-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
MRPL44NM_022915.5 linkc.467T>G p.Leu156Arg missense_variant Exon 2 of 4 ENST00000258383.4 NP_075066.1 Q9H9J2A1MA90
MRPL44XM_011511668.3 linkc.425T>G p.Leu142Arg missense_variant Exon 2 of 4 XP_011509970.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
MRPL44ENST00000258383.4 linkc.467T>G p.Leu156Arg missense_variant Exon 2 of 4 1 NM_022915.5 ENSP00000258383.3 Q9H9J2

Frequencies

GnomAD3 genomes
AF:
0.000158
AC:
24
AN:
152206
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000241
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:
0.000565
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000250
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000219
AC:
55
AN:
251422
Hom.:
0
AF XY:
0.000250
AC XY:
34
AN XY:
135880
show subpopulations
Gnomad AFR exome
AF:
0.0000615
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.0000924
Gnomad NFE exome
AF:
0.000440
Gnomad OTH exome
AF:
0.000326
GnomAD4 exome
AF:
0.000357
AC:
522
AN:
1461880
Hom.:
0
Cov.:
31
AF XY:
0.000351
AC XY:
255
AN XY:
727238
show subpopulations
Gnomad4 AFR exome
AF:
0.0000597
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.000318
Gnomad4 NFE exome
AF:
0.000447
Gnomad4 OTH exome
AF:
0.0000993
GnomAD4 genome
AF:
0.000158
AC:
24
AN:
152206
Hom.:
0
Cov.:
33
AF XY:
0.000161
AC XY:
12
AN XY:
74354
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.000565
Gnomad4 NFE
AF:
0.000250
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000286
Hom.:
0
Bravo
AF:
0.000125
TwinsUK
AF:
0.000270
AC:
1
ALSPAC
AF:
0.000519
AC:
2
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000349
AC:
3
ExAC
AF:
0.000280
AC:
34
EpiCase
AF:
0.000218
EpiControl
AF:
0.000296

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Infantile hypertrophic cardiomyopathy due to MRPL44 deficiency Pathogenic:4
Apr 29, 2014
UCLA Clinical Genomics Center, UCLA
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Feb 10, 2022
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Variant summary: MRPL44 c.467T>G (p.Leu156Arg) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00022 in 251422 control chromosomes. c.467T>G has been reported in the literature in multiple individuals. The variant has been reported in the homozygous state in siblings with hypertrophic cardiomyopathy as a leading symptom and combined respiratory complex I and IV deficiency in heart tissue and isolated complex IV deficiency in fibroblasts (Carroll_2013), in a patient with mitochondrial myopathy with second allele not specified (Florian_2015), in patients with hypertrophic cardiomyopathy and additional neurological clinical features (Distelmaier_2015), and in a patient with mitochondrial disease without other mutations in mtDNA (Legati_2016). These data indicate that the variant is very likely to be associated with disease. Experimental evidence demonstrates a damaging effect of the variant including a severe reduction of MRPL44 protein levels in patient fibroblasts and altered assembly of the large ribosomal subunit and stability of 16S rRNA with complex IV deficiency, which is rescued by retroviral expression of wild-type MRPL44 (Carroll_2013). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Mar 01, 2013
OMIM
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: literature only

- -

-
Genomics England Pilot Project, Genomics England
Significance: Likely pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

not provided Pathogenic:2
Mar 21, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces leucine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 156 of the MRPL44 protein (p.Leu156Arg). This variant is present in population databases (rs143697995, gnomAD 0.04%). This missense change has been observed in individuals with combined oxidative phosphorylation deficiency (PMID: 23315540, 25797485). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 64624). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt MRPL44 protein function with a negative predictive value of 80%. Studies have shown that this missense change alters MRPL44 gene expression (PMID: 23315540). For these reasons, this variant has been classified as Pathogenic. -

Mar 05, 2025
GeneDx
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Published functional studies demonstrate a severe reduction of MRPL44 protein levels in patient fibroblasts and altered assembly of the large ribosomal subunit and stability of 16S rRNA with complex IV deficiency, which is rescued by retroviral expression of wild-type MRPL44 (PMID: 23315540); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 23315540, 25326637, 25797485, 34426522, 33742325, 34140213, 34758253, 26001801, 34277617, 33742171, 35772644, 34732400, 26968897, 33726816, 38950860, 37628588, 38020895) -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.72
BayesDel_addAF
Uncertain
0.039
T
BayesDel_noAF
Pathogenic
0.15
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Benign
0.25
T
Eigen
Uncertain
0.62
Eigen_PC
Uncertain
0.57
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Benign
0.82
T
M_CAP
Uncertain
0.10
D
MetaRNN
Pathogenic
0.84
D
MetaSVM
Benign
-0.51
T
MutationAssessor
Uncertain
2.3
M
PrimateAI
Benign
0.46
T
PROVEAN
Pathogenic
-4.6
D
REVEL
Uncertain
0.47
Sift
Uncertain
0.0020
D
Sift4G
Uncertain
0.0050
D
Polyphen
0.99
D
Vest4
0.97
MVP
0.85
MPC
0.74
ClinPred
0.69
D
GERP RS
5.7
Varity_R
0.94
gMVP
0.89

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.020
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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs143697995; hg19: chr2-224824538; API