rs768402414

Variant names:

• chr2-75655272-C-T
• rs768402414
• NM_014763.4:c.866C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_014763.4(MRPL19):​c.866C>T​(p.Ser289Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000105 in 1,611,576 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: 𝑓 0.000013 (0 hom., cov: 30)
  • Exomes 𝑓: 0.000010 (0 hom.)
• Consequence: MRPL19 NM_014763.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.15
• Publications: 0 publications found

Genes affected

MRPL19 (HGNC:14052): (mitochondrial ribosomal protein L19) 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]

GCFC2 (HGNC:1317): (GC-rich sequence DNA-binding factor 2) The first mRNA transcript isolated for this gene was part of an artificial chimera derived from two distinct gene transcripts and a primer used in the cloning process (see Genbank accession M29204). A positively charged amino terminus present only in the chimera was determined to bind GC-rich DNA, thus mistakenly thought to identify a transcription factor gene. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.14637509).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014763.4. 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
	MRPL19	NM_014763.4	MANE Select	c.866C>T	p.Ser289Leu	missense	Exon 6 of 6	NP_055578.2	P49406

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MRPL19	ENST00000393909.7	TSL:1 MANE Select	c.866C>T	p.Ser289Leu	missense	Exon 6 of 6	ENSP00000377486.2	P49406
	MRPL19	ENST00000409374.5	TSL:5	c.866C>T	p.Ser289Leu	missense	Exon 6 of 7	ENSP00000387284.1	P49406
	MRPL19	ENST00000884931.1		c.866C>T	p.Ser289Leu	missense	Exon 6 of 7	ENSP00000554990.1

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 151792 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.0000242

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000242 AC: 6 AN: 248440 AF XY: 0.0000297

Gnomad AFR exome AF: 0.000130

Gnomad AMR exome AF: 0.0000292

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000886

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000103 AC: 15 AN: 1459784 Hom.: 0 Cov.: 34 AF XY: 0.0000110 AC XY: 8 AN XY: 726246

African (AFR) AF: 0.0000300 AC: 1 AN: 33376

American (AMR) AF: 0.0000224 AC: 1 AN: 44560

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26070

East Asian (EAS) AF: 0.00 AC: 0 AN: 39634

South Asian (SAS) AF: 0.0000931 AC: 8 AN: 85952

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53382

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5662

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1110832

Other (OTH) AF: 0.0000166 AC: 1 AN: 60316

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 151792 Hom.: 0 Cov.: 30 AF XY: 0.0000270 AC XY: 2 AN XY: 74148

African (AFR) AF: 0.0000242 AC: 1 AN: 41342

American (AMR) AF: 0.00 AC: 0 AN: 15246

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4808

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10494

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67938

Other (OTH) AF: 0.00 AC: 0 AN: 2084

Alfa AF: 0.0000660 Hom.: 0

Bravo AF: 0.0000151

ExAC AF: 0.00000828 AC: 1

EpiCase AF: 0.0000547

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.016	T
Eigen	Benign	0.10
Eigen_PC	Benign	0.068
FATHMM_MKL	Benign	0.51	D
LIST_S2	Benign	0.73	T
M_CAP	Benign	0.0073	T
MetaRNN	Benign	0.15	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		2.1
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.11	N
REVEL	Benign	0.10
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.0090	D
Polyphen		0.97	D
Vest4		0.059
MutPred		0.24		Loss of glycosylation at S289 (P = 0.0138)
MVP		0.73
MPC		0.39
ClinPred		0.19	T
GERP RS		4.2
PromoterAI		-0.0082	Neutral
Varity_R		0.11
gMVP		0.53
Mutation Taster		=96/4	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.14		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs768402414; hg19: chr2-75882398;