chr2-223957564-T-A

Position:

• chr2-223957564-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_022915.5(MRPL44):​c.92T>A​(p.Val31Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,598 control chromosomes in the GnomAD database, with no homozygous occurrence. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: MRPL44 NM_022915.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.736

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MRPL44	NM_022915.5	c.92T>A	p.Val31Glu	missense_variant	1/4	ENST00000258383.4
MRPL44	XM_011511668.3	c.138-1970T>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MRPL44	ENST00000258383.4	c.92T>A	p.Val31Glu	missense_variant	1/4	1	NM_022915.5	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461598 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727140

Gnomad4 AFR exome AF: 0.00

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: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jun 05, 2022	This sequence change replaces valine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 31 of the MRPL44 protein (p.Val31Glu). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with MRPL44-related conditions. ClinVar contains an entry for this variant (Variation ID: 1396119). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Feb 28, 2023	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	0.0062	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	19
DANN	Benign	0.88
DEOGEN2	Benign	0.014	T
Eigen	Benign	0.18
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.54	T
M_CAP	Benign	0.033	D
MetaRNN	Uncertain	0.48	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Uncertain	2.2	M
MutationTaster	Benign	0.65	D
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-0.66	N
REVEL	Benign	0.14
Sift	Benign	0.55	T
Sift4G	Benign	0.98	T
Polyphen		0.95	P
Vest4		0.60
MutPred		0.33		Gain of solvent accessibility (P = 9e-04);
MVP		0.67
MPC		0.30
ClinPred		0.43	T
GERP RS		4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.58
gMVP		0.55

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: rs1050354867; hg19: chr2-224822281;