chr1-46612982-C-T

Variant names:

• chr1-46612982-C-T
• NM_201403.3:c.340G>A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_201403.3(MOB3C):​c.340G>A​(p.Ala114Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,048 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A114S) 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: Not reported in ClinVar
• Conservation: PhyloP100: 7.89

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.975

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MOB3C	NM_201403.3	c.340G>A	p.Ala114Thr	missense_variant	Exon 2 of 4	ENST00000319928.9	NP_958805.1
MOB3C	NM_145279.5	c.340G>A	p.Ala114Thr	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.340G>A	p.Ala114Thr	missense_variant	Exon 2 of 4	2	NM_201403.3	ENSP00000315113.3
MOB3C	ENST00000271139.13	c.340G>A	p.Ala114Thr	missense_variant	Exon 2 of 4	1		ENSP00000271139.9
MOB3C	ENST00000371940.1	c.340G>A	p.Ala114Thr	missense_variant	Exon 1 of 3	1		ENSP00000361008.2
MKNK1	ENST00000531769.6	c.-171+3729G>A		intron_variant	Intron 1 of 4	4		ENSP00000434021.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459048 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 725540

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: 9.01e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.47
CADD	Uncertain	23
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.45	T;T;T
Eigen	Pathogenic	0.82
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.97	D;D;.
M_CAP	Benign	0.057	D
MetaRNN	Pathogenic	0.98	D;D;D
MetaSVM	Uncertain	0.66	D
MutationAssessor	Pathogenic	4.1	H;.;H
PrimateAI	Uncertain	0.73	T
PROVEAN	Uncertain	-3.9	D;D;N
REVEL	Pathogenic	0.91
Sift	Pathogenic	0.0	D;D;T
Sift4G	Uncertain	0.0020	D;D;D
Polyphen		1.0	D;.;D
Vest4		0.95
MutPred		0.87		Gain of phosphorylation at A114 (P = 0.0068);.;Gain of phosphorylation at A114 (P = 0.0068);
MVP		0.73
MPC		1.2
ClinPred		1.0	D
GERP RS		5.3
Varity_R		0.72
gMVP		0.75

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: chr1-47078654;