Genetic Variant MON1A:p.Arg486His (chr3-49909323-C-T) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_032355.4(MON1A):c.1457G>A(p.Arg486His) variant causes a missense change. The variant allele was found at a frequency of 0.0000675 in 1,613,926 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000072 ( 0 hom. )

Consequence

MON1A
NM_032355.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.10

Variant links:

Genes affected

MON1A (HGNC:28207): (MON1 homolog A, secretory trafficking associated) Enables guanyl-nucleotide exchange factor activity. Predicted to be involved in protein secretion. Predicted to act upstream of or within cellular iron ion homeostasis and protein transport. Part of Mon1-Ccz1 complex. [provided by Alliance of Genome Resources, Apr 2022]

MON1A links:

ENSG00000228008 (HGNC:):

ENSG00000228008 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.3138504).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MON1A	NM_032355.4 link	c.1457G>A	p.Arg486His	missense_variant	Exon 5 of 6	ENST00000296473.8	NP_115731.3	Q86VX9-5
MON1A	NM_001142501.2 link	c.971G>A	p.Arg324His	missense_variant	Exon 4 of 5		NP_001135973.2	Q86VX9-2
MON1A	XM_006713345.5 link	c.1457G>A	p.Arg486His	missense_variant	Exon 5 of 6		XP_006713408.1	Q86VX9-5
MON1A	XM_011534160.2 link	c.1457G>A	p.Arg486His	missense_variant	Exon 5 of 6		XP_011532462.1	Q86VX9-5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MON1A	ENST00000296473.8 link	c.1457G>A	p.Arg486His	missense_variant	Exon 5 of 6	1	NM_032355.4	ENSP00000296473.4		Q86VX9-5

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152166

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000199

AC:

AN:

251312

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135874

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

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:

0.0000264

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000718

AC:

105

AN:

1461760

Hom.:

Cov.:

AF XY:

0.0000688

AC XY:

AN XY:

727188

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000101

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000872

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152166

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74334

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000329

Hom.:

Bravo

AF:

0.0000302

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Aug 05, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1748G>A (p.R583H) alteration is located in exon 5 (coding exon 5) of the MON1A gene. This alteration results from a G to A substitution at nucleotide position 1748, causing the arginine (R) at amino acid position 583 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

Uncertain

0.38

BayesDel_addAF

Benign

-0.088

BayesDel_noAF

Benign

-0.26

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.080

.;.;.;.;T

Eigen

Uncertain

0.28

Eigen_PC

Uncertain

0.39

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.91

.;D;D;D;D

M_CAP

Benign

0.0038

MetaRNN

Benign

0.31

T;T;T;T;T

MetaSVM

Benign

-0.84

MutationAssessor

Benign

1.5

L;L;.;.;.

PrimateAI

Uncertain

0.59

PROVEAN

Uncertain

-3.3

.;.;D;D;D

REVEL

Uncertain

0.40

Sift

Benign

0.10

.;.;T;T;T

Sift4G

Benign

0.12

.;.;T;T;T

Vest4

0.60, 0.37, 0.34

MVP

0.66

MPC

1.0

ClinPred

0.73

GERP RS

5.5

Varity_R

0.13

gMVP

0.49

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