4-83461030-T-C

Variant names:

• chr4-83461030-T-C
• rs780821291
• NM_016067.4:c.350T>C

Variant summary

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

The NM_016067.4(MRPS18C):​c.350T>C​(p.Met117Thr) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000685 in 1,460,132 control chromosomes in the GnomAD database, with no homozygous occurrence. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000068 (0 hom.)
• Consequence: MRPS18C NM_016067.4 missense, splice_region
• Scores: Splicing: ADA: 0.001776
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.97

Genes affected

MRPS18C (HGNC:16633): (mitochondrial ribosomal protein S18C) 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 S18P family. The encoded protein is one of three that has significant sequence similarity to bacterial S18 proteins. The primary sequences of the three human mitochondrial S18 proteins are no more closely related to each other than they are to the prokaryotic S18 proteins. Pseudogenes corresponding to this gene are found on chromosomes 8p, 12p, 15q, and 22q. [provided by RefSeq, Jul 2008]

ABRAXAS1 (HGNC:25829): (abraxas 1, BRCA1 A complex subunit) This gene encodes a protein that binds to the C-terminal repeats of breast cancer 1 (BRCA1) through a phospho-SXXF motif. The encoded protein recruits ubiquitin interaction motif containing 1 protein to BRCA1 protein and is required for DNA damage resistance, DNA repair, and cell cycle checkpoint control. Pseudogenes of this gene are found on chromosomes 3 and 8. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Sep 2016]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MRPS18C	NM_016067.4	c.350T>C	p.Met117Thr	missense_variant, splice_region_variant	Exon 5 of 6	ENST00000295491.9	NP_057151.1
ABRAXAS1	NM_139076.3	c.*1439A>G		3_prime_UTR_variant	Exon 9 of 9	ENST00000321945.12	NP_620775.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MRPS18C	ENST00000295491.9	c.350T>C	p.Met117Thr	missense_variant, splice_region_variant	Exon 5 of 6	1	NM_016067.4	ENSP00000295491.4
ABRAXAS1	ENST00000321945	c.*1439A>G		3_prime_UTR_variant	Exon 9 of 9	1	NM_139076.3	ENSP00000369857.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000440 AC: 11 AN: 250064 Hom.: 0 AF XY: 0.0000443 AC XY: 6 AN XY: 135324

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000292

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000545

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000685 AC: 10 AN: 1460132 Hom.: 0 Cov.: 31 AF XY: 0.00000688 AC XY: 5 AN XY: 726436

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000203

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.0000741 AC: 9

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 04, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.350T>C (p.M117T) alteration is located in exon 5 (coding exon 5) of the MRPS18C gene. This alteration results from a T to C substitution at nucleotide position 350, causing the methionine (M) at amino acid position 117 to be replaced by a threonine (T). 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	Uncertain	0.53
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.16
CADD	Uncertain	23
DANN	Benign	0.82
DEOGEN2	Benign	0.095	T;.
Eigen	Benign	0.058
Eigen_PC	Benign	0.15
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.55	T;T
M_CAP	Benign	0.012	T
MetaRNN	Uncertain	0.46	T;T
MetaSVM	Benign	-0.53	T
MutationAssessor	Uncertain	2.3	M;.
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-2.0	N;D
REVEL	Uncertain	0.31
Sift	Benign	0.22	T;T
Sift4G	Benign	0.27	T;T
Polyphen		0.0010	B;.
Vest4		0.71
MutPred		0.70		Gain of catalytic residue at M120 (P = 0.038);.;
MVP		0.16
MPC		0.065
ClinPred		0.094	T
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.19
gMVP		0.58

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0018
dbscSNV1_RF	Benign	0.018
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: rs780821291; hg19: chr4-84382183;