Genetic Variant MOS:p.Cys320Tyr (chr8-56113024-C-T) – ACMG Classification: Likely_pathogenic (7 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2PP2PP3_Strong

The NM_005372.1(MOS):c.959G>A(p.Cys320Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.000000696 in 1,437,206 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. C320F) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.0e-7 ( 0 hom. )

Consequence

MOS
NM_005372.1 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.47

Publications

0 publications found

Variant links:

Genes affected

MOS (HGNC:7199): (MOS proto-oncogene, serine/threonine kinase) MOS is a serine/threonine kinase that activates the MAP kinase cascade through direct phosphorylation of the MAP kinase activator MEK (MAP2K1; MIM 176872) (Prasad et al., 2008 [PubMed 18246541]).[supplied by OMIM, Jul 2009]

MOS Gene-Disease associations (from GenCC):

oocyte/zygote/embryo maturation arrest 20
Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

MOS links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 8 curated pathogenic missense variants (we use a threshold of 10). The gene has 1 curated benign missense variants. Gene score misZ: 1.1461 (below the threshold of 3.09). Trascript score misZ: 0.91545 (below the threshold of 3.09). GenCC associations: The gene is linked to oocyte/zygote/embryo maturation arrest 20.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.984

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005372.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MOS	NM_005372.1	MANE Select	c.959G>A	p.Cys320Tyr	missense	Exon 1 of 1	NP_005363.1	P00540

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MOS	ENST00000311923.1	TSL:6 MANE Select	c.959G>A	p.Cys320Tyr	missense	Exon 1 of 1	ENSP00000310722.1	P00540

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.96e-7

AC:

AN:

1437206

Hom.:

Cov.:

AF XY:

0.00000140

AC XY:

AN XY:

713022

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32258

American (AMR)

AF:

0.00

AC:

AN:

39380

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24782

East Asian (EAS)

AF:

0.00

AC:

AN:

39408

South Asian (SAS)

AF:

0.0000120

AC:

AN:

83172

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52636

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5648

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1100718

Other (OTH)

AF:

0.00

AC:

AN:

59204

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.84

BayesDel_addAF

Pathogenic

0.42

BayesDel_noAF

Pathogenic

0.37

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.52

Eigen

Pathogenic

0.72

Eigen_PC

Uncertain

0.59

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.50

M_CAP

Pathogenic

0.48

MetaRNN

Pathogenic

0.98

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

4.0

PhyloP100

5.5

PrimateAI

Uncertain

0.57

PROVEAN

Uncertain

-3.6

REVEL

Pathogenic

0.90

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0010

Polyphen

1.0

Vest4

0.83

MutPred

0.86

Loss of catalytic residue at W321 (P = 0.0024)

MVP

1.0

MPC

2.0

ClinPred

1.0

GERP RS

4.9

Varity_R

0.84

gMVP

0.98

Mutation Taster

=18/82

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over