1-46610102-A-T

Position:

• chr1-46610102-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_201403.3(MOB3C):​c.521T>A​(p.Leu174His) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MOB3C NM_201403.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.85

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.24719048).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MOB3C	NM_201403.3	c.521T>A	p.Leu174His	missense_variant	3/4	ENST00000319928.9	NP_958805.1
MOB3C	NM_145279.5	c.521T>A	p.Leu174His	missense_variant	3/4		NP_660322.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MOB3C	ENST00000319928.9	c.521T>A	p.Leu174His	missense_variant	3/4	2	NM_201403.3	ENSP00000315113	P1
MOB3C	ENST00000271139.13	c.521T>A	p.Leu174His	missense_variant	3/4	1		ENSP00000271139	P1
MOB3C	ENST00000371940.1	c.521T>A	p.Leu174His	missense_variant	2/3	1		ENSP00000361008	P1
MKNK1	ENST00000531769.6	c.-171+6609T>A		intron_variant		4		ENSP00000434021

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 19, 2024

The c.677T>A (p.L226H) alteration is located in exon 3 (coding exon 3) of the MOB3C gene. This alteration results from a T to A substitution at nucleotide position 677, causing the leucine (L) at amino acid position 226 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	Benign	0.27
BayesDel_addAF	Benign	-0.0062	T
BayesDel_noAF	Benign	-0.25
CADD	Uncertain	24
DANN	Benign	0.93
DEOGEN2	Benign	0.041	T;T;T
Eigen	Benign	-0.061
Eigen_PC	Benign	0.14
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.88	D;D;.
M_CAP	Benign	0.0043	T
MetaRNN	Benign	0.25	T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.68	N;.;N
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.79	T
PROVEAN	Benign	-1.9	N;N;.
REVEL	Benign	0.12
Sift	Benign	0.17	T;T;.
Sift4G	Benign	0.27	T;T;T
Polyphen		0.0	B;.;B
Vest4		0.53
MutPred		0.52		Gain of disorder (P = 0.0062);.;Gain of disorder (P = 0.0062);
MVP		0.42
MPC		0.55
ClinPred		0.67	D
GERP RS		5.2
Varity_R		0.18
gMVP		0.28

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: rs1675440037; hg19: chr1-47075774;