1-228107769-C-T

Variant names:

• chr1-228107769-C-T
• rs1487205388
• NM_181463.3:c.127G>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_181463.3(MRPL55):​c.127G>A​(p.Val43Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,916 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 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: MRPL55 NM_181463.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.261

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.19757059).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MRPL55	NM_181463.3	c.127G>A	p.Val43Met	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.127G>A	p.Val43Met	missense_variant	Exon 4 of 5	2	NM_181463.3	ENSP00000337342.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000399 AC: 1 AN: 250350 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135754

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 SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460916 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 726782

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 12, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.235G>A (p.V79M) 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 235, causing the valine (V) at amino acid position 79 to be replaced by a methionine (M). 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	0.15
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	8.5
DANN	Benign	0.97
DEOGEN2	Benign	0.011	T;T;T;T;.;T;T;T;T;T;T;T;T;T;T;T;T;.;.;.
Eigen	Benign	-0.73
Eigen_PC	Benign	-0.89
FATHMM_MKL	Benign	0.093	N
LIST_S2	Benign	0.73	.;.;.;T;.;.;.;.;.;.;.;.;.;.;.;.;.;T;T;T
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.14	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Uncertain	2.1	M;M;M;M;.;M;M;M;M;M;M;M;M;M;M;M;M;.;.;.
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-0.63	N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N
REVEL	Benign	0.12
Sift	Uncertain	0.022	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
Sift4G	Uncertain	0.030	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;.;D
Polyphen		0.45	P;P;P;P;P;P;P;P;P;P;P;P;P;P;P;P;P;P;.;.
Vest4		0.080
MutPred		0.46		Gain of catalytic residue at V43 (P = 0.0223);Gain of catalytic residue at V43 (P = 0.0223);Gain of catalytic residue at V43 (P = 0.0223);Gain of catalytic residue at V43 (P = 0.0223);.;Gain of catalytic residue at V43 (P = 0.0223);Gain of catalytic residue at V43 (P = 0.0223);Gain of catalytic residue at V43 (P = 0.0223);Gain of catalytic residue at V43 (P = 0.0223);Gain of catalytic residue at V43 (P = 0.0223);Gain of catalytic residue at V43 (P = 0.0223);Gain of catalytic residue at V43 (P = 0.0223);Gain of catalytic residue at V43 (P = 0.0223);Gain of catalytic residue at V43 (P = 0.0223);Gain of catalytic residue at V43 (P = 0.0223);Gain of catalytic residue at V43 (P = 0.0223);Gain of catalytic residue at V43 (P = 0.0223);.;Gain of catalytic residue at V43 (P = 0.0223);Gain of catalytic residue at V43 (P = 0.0223);
MVP		0.12
ClinPred		0.079	T
GERP RS		-0.54
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.092
gMVP		0.086

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1487205388; hg19: chr1-228295470;