1-228107832-C-T

Variant names:

• chr1-228107832-C-T
• rs1206394772
• NM_181463.3:c.64G>A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_181463.3(MRPL55):​c.64G>A​(p.Ala22Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000131 in 152,210 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: 𝑓 0.000013 (0 hom., cov: 33)
• Consequence: MRPL55 NM_181463.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.630

Genes affected

MRPL55 (HGNC:16686): (mitochondrial ribosomal protein L55) 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. Multiple transcript variants encoding two different isoforms were identified through sequence analysis. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.03590569).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MRPL55	NM_181463.3	c.64G>A	p.Ala22Thr	missense_variant	Exon 4 of 5	ENST00000336520.8	NP_852128.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MRPL55	ENST00000336520.8	c.64G>A	p.Ala22Thr	missense_variant	Exon 4 of 5	2	NM_181463.3	ENSP00000337342.3

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152210 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000483

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

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152210 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74366

Gnomad4 AFR AF: 0.0000483

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 20, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.172G>A (p.A58T) alteration is located in exon 5 (coding exon 3) of the MRPL55 gene. This alteration results from a G to A substitution at nucleotide position 172, causing the alanine (A) at amino acid position 58 to be replaced by a threonine (T). 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	0.071
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	0.36
DANN	Benign	0.65
DEOGEN2	Benign	0.0045	T;T;T;T;.;T;T;T;T;T;T;T;T;T;T;T;T;.;.;.;.
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.030	N
LIST_S2	Benign	0.34	.;.;.;T;.;.;.;.;.;.;.;.;.;.;.;.;.;T;T;T;T
M_CAP	Benign	0.0035	T
MetaRNN	Benign	0.036	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.22	N;N;N;N;.;N;N;N;N;N;N;N;N;N;N;N;N;.;.;.;.
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-0.45	N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;.
REVEL	Benign	0.024
Sift	Benign	1.0	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;.
Sift4G	Benign	0.89	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;.;T;.
Polyphen		0.0030	B;B;B;B;B;B;B;B;B;B;B;B;B;B;B;B;B;B;.;.;.
Vest4		0.048
MutPred		0.36		Gain of phosphorylation at A22 (P = 0.0305);Gain of phosphorylation at A22 (P = 0.0305);Gain of phosphorylation at A22 (P = 0.0305);Gain of phosphorylation at A22 (P = 0.0305);.;Gain of phosphorylation at A22 (P = 0.0305);Gain of phosphorylation at A22 (P = 0.0305);Gain of phosphorylation at A22 (P = 0.0305);Gain of phosphorylation at A22 (P = 0.0305);Gain of phosphorylation at A22 (P = 0.0305);Gain of phosphorylation at A22 (P = 0.0305);Gain of phosphorylation at A22 (P = 0.0305);Gain of phosphorylation at A22 (P = 0.0305);Gain of phosphorylation at A22 (P = 0.0305);Gain of phosphorylation at A22 (P = 0.0305);Gain of phosphorylation at A22 (P = 0.0305);Gain of phosphorylation at A22 (P = 0.0305);.;Gain of phosphorylation at A22 (P = 0.0305);Gain of phosphorylation at A22 (P = 0.0305);Gain of phosphorylation at A22 (P = 0.0305);
MVP		0.12
ClinPred		0.074	T
GERP RS		-8.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.012
gMVP		0.087

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: rs1206394772; hg19: chr1-228295533;