1-228107668-C-T

Variant names:

• chr1-228107668-C-T
• rs34055261
• NM_181463.3:c.228G>A

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 2P and 10B. PP3_Moderate BP6_Moderate BS1 BS2

The NM_181463.3(MRPL55):​c.228G>A​(p.Ala76Ala) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00223 in 1,612,514 control chromosomes in the GnomAD database, including 79 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Benign (★). Synonymous variant affecting the same amino acid position (i.e. A76A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.012 (42 hom., cov: 33)
  • Exomes 𝑓: 0.0012 (37 hom.)
• Consequence: MRPL55 NM_181463.3 splice_region, synonymous
• Scores: Splicing: ADA: 0.9999
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0130
• Publications: 4 publications found

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

Our verdict: Benign. The variant received -8 ACMG points.

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. Scorers claiming Uncertain: max_spliceai. No scorers claiming Benign.
• BP6: Variant 1-228107668-C-T is Benign according to our data. Variant chr1-228107668-C-T is described in ClinVar as Benign. ClinVar VariationId is 775678.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0118 (1792/152354) while in subpopulation AFR AF = 0.0412 (1711/41578). AF 95% confidence interval is 0.0395. There are 42 homozygotes in GnomAd4. There are 849 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 42 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_181463.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MRPL55	NM_181463.3	MANE Select	c.228G>A	p.Ala76Ala	splice_region synonymous	Exon 4 of 5	NP_852128.1	Q7Z7F7-1
	MRPL55	NM_181462.3		c.336G>A	p.Ala112Ala	splice_region synonymous	Exon 5 of 6	NP_852127.2	Q7Z7F7-2
	MRPL55	NM_001321284.2		c.228G>A	p.Ala76Ala	splice_region synonymous	Exon 4 of 5	NP_001308213.1	Q7Z7F7-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MRPL55	ENST00000336520.8	TSL:2 MANE Select	c.228G>A	p.Ala76Ala	splice_region synonymous	Exon 4 of 5	ENSP00000337342.3	Q7Z7F7-1
	MRPL55	ENST00000366738.5	TSL:1	c.336G>A	p.Ala112Ala	splice_region synonymous	Exon 4 of 5	ENSP00000355699.1	Q7Z7F7-2
	MRPL55	ENST00000366735.5	TSL:1	c.228G>A	p.Ala76Ala	splice_region synonymous	Exon 2 of 3	ENSP00000355696.1	Q7Z7F7-1

Frequencies

GnomAD3 genomes AF: 0.0117 AC: 1787 AN: 152236 Hom.: 42 Cov.: 33

Gnomad AFR AF: 0.0412

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00399

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00525

GnomAD2 exomes AF: 0.00313 AC: 780 AN: 249512 AF XY: 0.00230

Gnomad AFR exome AF: 0.0425

Gnomad AMR exome AF: 0.00203

Gnomad ASJ exome AF: 0.0000998

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000978

Gnomad OTH exome AF: 0.00213

GnomAD4 exome AF: 0.00123 AC: 1798 AN: 1460160 Hom.: 37 Cov.: 31 AF XY: 0.00108 AC XY: 784 AN XY: 726388

African (AFR) AF: 0.0434 AC: 1451 AN: 33442

American (AMR) AF: 0.00221 AC: 99 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.0000765 AC: 2 AN: 26132

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39686

South Asian (SAS) AF: 0.000174 AC: 15 AN: 86192

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52502

Middle Eastern (MID) AF: 0.00208 AC: 11 AN: 5292

European-Non Finnish (NFE) AF: 0.0000621 AC: 69 AN: 1111902

Other (OTH) AF: 0.00249 AC: 150 AN: 60314

GnomAD4 genome AF: 0.0118 AC: 1792 AN: 152354 Hom.: 42 Cov.: 33 AF XY: 0.0114 AC XY: 849 AN XY: 74498

African (AFR) AF: 0.0412 AC: 1711 AN: 41578

American (AMR) AF: 0.00399 AC: 61 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 68034

Other (OTH) AF: 0.00520 AC: 11 AN: 2116

Alfa AF: 0.00321 Hom.: 34

Bravo AF: 0.0132

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000178

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	22
DANN	Benign	0.82
PhyloP100		-0.013
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=80/20	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.87
SpliceAI score (max)		0.48		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.48		Position offset: -18

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs34055261; hg19: chr1-228295369;