Genetic Variant MON1B:p.Arg255Cys (chr16-77194622-C-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_014940.4(MON1B):c.763C>T(p.Arg255Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000026 in 1,613,668 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000028 ( 0 hom. )

Consequence

MON1B
NM_014940.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.384

Variant links:

Genes affected

MON1B (HGNC:25020): (MON1 homolog B, secretory trafficking associated) Involved in early viral transcription and late viral transcription. Located in cytoplasm. Part of Mon1-Ccz1 complex. [provided by Alliance of Genome Resources, Apr 2022]

MON1B links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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=0.22904262).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MON1B	NM_014940.4 link	c.763C>T	p.Arg255Cys	missense_variant	Exon 4 of 6	ENST00000248248.8	NP_055755.1	Q7L1V2-1Q6ZR87
MON1B	NM_001286639.2 link	c.436C>T	p.Arg146Cys	missense_variant	Exon 3 of 5		NP_001273568.1	Q7L1V2E7EW32Q6ZR87B4DKA0
MON1B	NM_001286640.2 link	c.325C>T	p.Arg109Cys	missense_variant	Exon 2 of 4		NP_001273569.1	Q7L1V2-2Q6ZR87

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MON1B	ENST00000248248.8 link	c.763C>T	p.Arg255Cys	missense_variant	Exon 4 of 6	1	NM_014940.4	ENSP00000248248.3		Q7L1V2-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152198

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000282

AC:

AN:

248650

Hom.:

AF XY:

0.0000520

AC XY:

AN XY:

134666

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000536

Gnomad OTH exome

AF:

0.000164

GnomAD4 exome

AF:

0.0000281

AC:

AN:

1461470

Hom.:

Cov.:

AF XY:

0.0000303

AC XY:

AN XY:

727052

show subpopulations

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:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000351

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152198

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74338

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000676

Hom.:

Bravo

AF:

0.0000302

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Oct 01, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.763C>T (p.R255C) alteration is located in exon 4 (coding exon 3) of the MON1B gene. This alteration results from a C to T substitution at nucleotide position 763, causing the arginine (R) at amino acid position 255 to be replaced by a cysteine (C). 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

0.16

BayesDel_addAF

Benign

-0.088

BayesDel_noAF

Benign

-0.18

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.037

T;T;.;.

Eigen

Benign

0.041

Eigen_PC

Benign

-0.049

FATHMM_MKL

Benign

0.41

LIST_S2

Pathogenic

0.98

D;D;D;D

M_CAP

Benign

0.013

MetaRNN

Benign

0.17

T;T;T;T

MetaSVM

Benign

-0.90

MutationAssessor

Benign

0.90

L;.;.;.

PrimateAI

Uncertain

0.75

PROVEAN

Benign

-0.64

N;N;N;N

REVEL

Benign

0.17

Sift

Benign

0.053

T;D;T;D

Sift4G

Uncertain

0.034

D;D;D;D

Polyphen

1.0

D;.;D;.

Vest4

0.21

MutPred

0.38

Gain of catalytic residue at R255 (P = 0.0319);Gain of catalytic residue at R255 (P = 0.0319);.;.;

MVP

0.46

MPC

1.3

ClinPred

0.33

GERP RS

3.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.075

gMVP

0.62

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over