2-95087433-A-G

Variant names:

• chr2-95087433-A-G
• rs759663474
• NM_031902.5:c.1217T>C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_031902.5(MRPS5):​c.1217T>C​(p.Leu406Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,894 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L406R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: MRPS5 NM_031902.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.21
• Publications: 0 publications found

Genes affected

MRPS5 (HGNC:14498): (mitochondrial ribosomal protein S5) 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 28S subunit protein that belongs to the ribosomal protein S5P family. Pseudogenes corresponding to this gene are found on chromosomes 4q, 5q, and 18q. [provided by RefSeq, Jul 2008]

ENSG00000289685 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.786

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_031902.5. 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
	MRPS5	NM_031902.5	MANE Select	c.1217T>C	p.Leu406Pro	missense	Exon 12 of 12	NP_114108.1	P82675-1
	MRPS5	NM_001321995.2		c.980T>C	p.Leu327Pro	missense	Exon 12 of 12	NP_001308924.1	A0A8Q3SIP9
	MRPS5	NM_001321996.2		c.719T>C	p.Leu240Pro	missense	Exon 12 of 12	NP_001308925.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MRPS5	ENST00000272418.7	TSL:1 MANE Select	c.1217T>C	p.Leu406Pro	missense	Exon 12 of 12	ENSP00000272418.2	P82675-1
	ENSG00000289685	ENST00000695456.1		n.*2096T>C		non_coding_transcript_exon	Exon 17 of 17	ENSP00000511928.1
	ENSG00000289685	ENST00000695456.1		n.*2096T>C		3_prime_UTR	Exon 17 of 17	ENSP00000511928.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461894 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727248

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1112012

Other (OTH) AF: 0.0000166 AC: 1 AN: 60396

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.33
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.17
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.18	T
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.069	D
MetaRNN	Pathogenic	0.79	D
MetaSVM	Benign	-0.56	T
MutationAssessor	Uncertain	2.8	M
PhyloP100		8.2
PrimateAI	Uncertain	0.57	T
PROVEAN	Uncertain	-3.3	D
REVEL	Uncertain	0.36
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0040	D
Polyphen		1.0	D
Vest4		0.96
MutPred		0.34		Loss of catalytic residue at L406 (P = 0.0048)
MVP		0.91
MPC		0.71
ClinPred		0.98	D
GERP RS		3.6
Varity_R		0.67
gMVP		0.88
Mutation Taster		=30/70	disease causing

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

Other links and lift over

dbSNP: rs759663474; hg19: chr2-95753178;