1-1402132-T-C

Position:

• chr1-1402132-T-C

Variant summary

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

The ENST00000344843.12(MRPL20):​c.401A>G​(p.Asp134Gly) variant causes a missense change. The variant allele was found at a frequency of 0.0000041 in 1,461,822 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: MRPL20 ENST00000344843.12 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.96

Genes affected

MRPL20 (HGNC:14478): (mitochondrial ribosomal protein L20) 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. A pseudogene corresponding to this gene is found on chromosome 21q. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jan 2016]

MRPL20 (HGNC:):

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=0.22289562).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MRPL20	NM_017971.4	c.401A>G	p.Asp134Gly	missense_variant	4/4	ENST00000344843.12	NP_060441.2
MRPL20	NM_001318485.2	c.*437A>G		3_prime_UTR_variant	4/4		NP_001305414.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MRPL20	ENST00000344843.12	c.401A>G	p.Asp134Gly	missense_variant	4/4	1	NM_017971.4	ENSP00000341082.7
MRPL20	ENST00000487659.1	n.1474A>G		non_coding_transcript_exon_variant	3/3	2
MRPL20	ENST00000493287.5	n.285A>G		non_coding_transcript_exon_variant	3/3	2
MRPL20	ENST00000492508.1	c.*437A>G		downstream_gene_variant		2		ENSP00000459994.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000410 AC: 6 AN: 1461822 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2 AN XY: 727212

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: 0.00000540

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 23, 2024

The c.401A>G (p.D134G) alteration is located in exon 4 (coding exon 4) of the MRPL20 gene. This alteration results from a A to G substitution at nucleotide position 401, causing the aspartic acid (D) at amino acid position 134 to be replaced by a glycine (G). 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	0.11
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.050
CADD	Uncertain	24
DANN	Benign	0.88
DEOGEN2	Benign	0.071	T
Eigen	Benign	-0.49
Eigen_PC	Benign	-0.37
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.0087	T
MetaRNN	Benign	0.22	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.7	L
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.58	T
PROVEAN	Uncertain	-2.4	N
REVEL	Benign	0.26
Sift	Benign	0.24	T
Sift4G	Benign	0.23	T
Polyphen		0.058	B
Vest4		0.38
MutPred		0.39		Gain of methylation at K136 (P = 0.0722);
MVP		0.51
MPC		0.11
ClinPred		0.70	D
GERP RS		4.0
Varity_R		0.31
gMVP		0.57

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: rs1645336174; hg19: chr1-1337512;