4-83459755-G-T

Variant names:

• chr4-83459755-G-T
• NM_016067.4:c.250G>T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_016067.4(MRPS18C):​c.250G>T​(p.Val84Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,457,338 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: MRPS18C NM_016067.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.934

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3696144).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MRPS18C	NM_016067.4	c.250G>T	p.Val84Phe	missense_variant	Exon 4 of 6	ENST00000295491.9	NP_057151.1
ABRAXAS1	NM_139076.3	c.*2714C>A		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.250G>T	p.Val84Phe	missense_variant	Exon 4 of 6	1	NM_016067.4	ENSP00000295491.4
ABRAXAS1	ENST00000321945	c.*2714C>A		3_prime_UTR_variant	Exon 9 of 9	1	NM_139076.3	ENSP00000369857.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1457338 Hom.: 0 Cov.: 29 AF XY: 0.00000138 AC XY: 1 AN XY: 724948

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: 0.0000117

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.85
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.030
CADD	Benign	21
DANN	Benign	0.96
DEOGEN2	Benign	0.32	T;.
Eigen	Benign	-0.61
Eigen_PC	Benign	-0.56
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Uncertain	0.91	D;D
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.37	T;T
MetaSVM	Benign	-0.64	T
MutationAssessor	Uncertain	2.6	M;.
PrimateAI	Benign	0.37	T
PROVEAN	Uncertain	-2.6	D;D
REVEL	Uncertain	0.30
Sift	Benign	0.069	T;D
Sift4G	Benign	0.13	T;D
Polyphen		0.0090	B;.
Vest4		0.64
MutPred		0.62		Loss of loop (P = 0.2897);.;
MVP		0.014
MPC		0.086
ClinPred		0.67	D
GERP RS		-1.4
Varity_R		0.16
gMVP		0.60

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr4-84380908;