1-46613027-G-T

Variant names:

• chr1-46613027-G-T
• rs1006451264
• NM_201403.3:c.295C>A

Variant summary

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

The NM_201403.3(MOB3C):​c.295C>A​(p.Arg99Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,461,518 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: MOB3C NM_201403.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.72

Genes affected

MOB3C (HGNC:29800): (MOB kinase activator 3C) The protein encoded by this gene is similar to the yeast Mob1 protein. Yeast Mob1 binds Mps1p, a protein kinase essential for spindle pole body duplication and mitotic checkpoint regulation. Alternatively spliced transcript variants encoding distinct isoforms have been observed. [provided by RefSeq, Jul 2008]

MKNK1 (HGNC:7110): (MAPK interacting serine/threonine kinase 1) This gene encodes a Ser/Thr protein kinase that interacts with, and is activated by ERK1 and p38 mitogen-activated protein kinases, and thus may play a role in the response to environmental stress and cytokines. This kinase may also regulate transcription by phosphorylating eIF4E via interaction with the C-terminal region of eIF4G. Alternatively spliced transcript variants have been noted for this gene. [provided by RefSeq, Jan 2012]

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
MOB3C	NM_201403.3	c.295C>A	p.Arg99Ser	missense_variant	Exon 2 of 4	ENST00000319928.9	NP_958805.1
MOB3C	NM_145279.5	c.295C>A	p.Arg99Ser	missense_variant	Exon 2 of 4		NP_660322.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MOB3C	ENST00000319928.9	c.295C>A	p.Arg99Ser	missense_variant	Exon 2 of 4	2	NM_201403.3	ENSP00000315113.3
MOB3C	ENST00000271139.13	c.295C>A	p.Arg99Ser	missense_variant	Exon 2 of 4	1		ENSP00000271139.9
MOB3C	ENST00000371940.1	c.295C>A	p.Arg99Ser	missense_variant	Exon 1 of 3	1		ENSP00000361008.2
MKNK1	ENST00000531769.6	c.-171+3684C>A		intron_variant	Intron 1 of 4	4		ENSP00000434021.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461518 Hom.: 0 Cov.: 33 AF XY: 0.00000275 AC XY: 2 AN XY: 727054

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.00000540

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000282 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 31, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.451C>A (p.R151S) alteration is located in exon 2 (coding exon 2) of the MOB3C gene. This alteration results from a C to A substitution at nucleotide position 451, causing the arginine (R) at amino acid position 151 to be replaced by a serine (S). 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	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.27
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.020	T;T;T
Eigen	Uncertain	0.19
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Benign	0.68	D
LIST_S2	Uncertain	0.97	D;D;.
M_CAP	Benign	0.0054	T
MetaRNN	Uncertain	0.58	D;D;D
MetaSVM	Benign	-0.80	T
MutationAssessor	Uncertain	2.5	M;.;M
PrimateAI	Uncertain	0.79	T
PROVEAN	Benign	-1.9	N;N;.
REVEL	Uncertain	0.40
Sift	Benign	0.31	T;T;.
Sift4G	Benign	0.41	T;T;T
Polyphen		0.45	B;.;B
Vest4		0.84
MutPred		0.48		Loss of MoRF binding (P = 0.0277);.;Loss of MoRF binding (P = 0.0277);
MVP		0.54
MPC		0.60
ClinPred		0.91	D
GERP RS		5.3
Varity_R		0.31
gMVP		0.77

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

Publications

LitVar

Other links and lift over

dbSNP: rs1006451264; hg19: chr1-47078699; COSMIC: COSV99596296;