1-46612955-C-G

Variant names:

• chr1-46612955-C-G
• NM_201403.3:c.367G>C

Variant summary

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

The NM_201403.3(MOB3C):​c.367G>C​(p.Asp123His) variant causes a missense change. The variant allele was found at a frequency of 0.000000693 in 1,441,966 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D123G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: MOB3C NM_201403.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.12

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.367G>C	p.Asp123His	missense_variant	Exon 2 of 4	ENST00000319928.9	NP_958805.1
MOB3C	NM_145279.5	c.367G>C	p.Asp123His	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.367G>C	p.Asp123His	missense_variant	Exon 2 of 4	2	NM_201403.3	ENSP00000315113.3
MOB3C	ENST00000271139.13	c.367G>C	p.Asp123His	missense_variant	Exon 2 of 4	1		ENSP00000271139.9
MOB3C	ENST00000371940.1	c.367G>C	p.Asp123His	missense_variant	Exon 1 of 3	1		ENSP00000361008.2
MKNK1	ENST00000531769.6	c.-171+3756G>C		intron_variant	Intron 1 of 4	4		ENSP00000434021.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.93e-7 AC: 1 AN: 1441966 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 714648

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000168

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 06, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.523G>C (p.D175H) alteration is located in exon 2 (coding exon 2) of the MOB3C gene. This alteration results from a G to C substitution at nucleotide position 523, causing the aspartic acid (D) at amino acid position 175 to be replaced by a histidine (H). 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	0.76
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.13
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.20	T;T;T
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Pathogenic	0.99	D;D;.
M_CAP	Benign	0.031	D
MetaRNN	Uncertain	0.59	D;D;D
MetaSVM	Uncertain	0.12	D
MutationAssessor	Pathogenic	3.4	M;.;M
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-4.7	D;D;.
REVEL	Uncertain	0.41
Sift	Uncertain	0.0050	D;D;.
Sift4G	Uncertain	0.0040	D;D;D
Polyphen		1.0	D;.;D
Vest4		0.71
MutPred		0.65		Gain of MoRF binding (P = 0.0668);.;Gain of MoRF binding (P = 0.0668);
MVP		0.67
MPC		1.2
ClinPred		0.99	D
GERP RS		5.3
Varity_R		0.69
gMVP		0.66

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-47078627;