1-175014815-C-G

Variant names:

• chr1-175014815-C-G
• rs901152195
• NM_022100.3:c.241G>C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_022100.3(MRPS14):​c.241G>C​(p.Asp81His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. D81N) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MRPS14 NM_022100.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.71
• Publications: 0 publications found

Genes affected

MRPS14 (HGNC:14049): (mitochondrial ribosomal protein S14) 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 S14P family. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Nov 2010]

MRPS14 Gene-Disease associations (from GenCC):

• combined oxidative phosphorylation deficiency 38

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.877

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_022100.3. 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
	MRPS14	NM_022100.3	MANE Select	c.241G>C	p.Asp81His	missense	Exon 3 of 3	NP_071383.1	O60783
	MRPS14	NR_037606.2		n.350G>C		non_coding_transcript_exon	Exon 3 of 3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MRPS14	ENST00000476371.1	TSL:1 MANE Select	c.241G>C	p.Asp81His	missense	Exon 3 of 3	ENSP00000420714.1	O60783
	MRPS14	ENST00000367677.3	TSL:1	n.*150G>C		non_coding_transcript_exon	Exon 3 of 3	ENSP00000431220.1	F2Z361
	MRPS14	ENST00000367677.3	TSL:1	n.*150G>C		3_prime_UTR	Exon 3 of 3	ENSP00000431220.1	F2Z361

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.46
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.78	D
Eigen	Pathogenic	0.98
Eigen_PC	Pathogenic	0.96
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Benign	0.027	D
MetaRNN	Pathogenic	0.88	D
MetaSVM	Uncertain	0.17	D
MutationAssessor	Pathogenic	3.7	H
PhyloP100		7.7
PrimateAI	Pathogenic	0.82	D
PROVEAN	Uncertain	-3.9	D
REVEL	Uncertain	0.51
Sift	Uncertain	0.011	D
Sift4G	Uncertain	0.018	D
Polyphen		1.0	D
Vest4		0.88
MutPred		0.58		Gain of catalytic residue at D81 (P = 0.0441)
MVP		0.65
MPC		1.1
ClinPred		1.0	D
GERP RS		6.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.54
gMVP		0.87
Mutation Taster		=49/51	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs901152195; hg19: chr1-174983951;