Genetic Variant MON1A:p.Arg431His (chr3-49910206-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_032355.4(MON1A):c.1292G>A(p.Arg431His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000157 in 1,461,766 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R431C) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.000016 ( 0 hom. )

Consequence

MON1A
NM_032355.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.17

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 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.19064894).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MON1A	NM_032355.4 link	c.1292G>A	p.Arg431His	missense_variant	Exon 4 of 6	ENST00000296473.8	NP_115731.3	Q86VX9-5
MON1A	NM_001142501.2 link	c.806G>A	p.Arg269His	missense_variant	Exon 3 of 5		NP_001135973.2	Q86VX9-2
MON1A	XM_006713345.5 link	c.1292G>A	p.Arg431His	missense_variant	Exon 4 of 6		XP_006713408.1	Q86VX9-5
MON1A	XM_011534160.2 link	c.1292G>A	p.Arg431His	missense_variant	Exon 4 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.1292G>A	p.Arg431His	missense_variant	Exon 4 of 6	1	NM_032355.4	ENSP00000296473.4		Q86VX9-5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000797

AC:

AN:

250988

Hom.:

AF XY:

0.00000737

AC XY:

AN XY:

135678

show subpopulations

Gnomad AFR exome

AF:

0.0000616

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:

0.00

Gnomad OTH exome

AF:

0.000164

GnomAD4 exome

AF:

0.0000157

AC:

AN:

1461766

Hom.:

Cov.:

AF XY:

0.0000124

AC XY:

AN XY:

727166

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000756

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000162

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000658

Hom.:

Bravo

AF:

0.00000756

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Nov 17, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1583G>A (p.R528H) alteration is located in exon 4 (coding exon 4) of the MON1A gene. This alteration results from a G to A substitution at nucleotide position 1583, causing the arginine (R) at amino acid position 528 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

0.072

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.43

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.027

.;.;.;.;T

Eigen

Benign

-0.0091

Eigen_PC

Benign

0.16

FATHMM_MKL

Uncertain

0.87

LIST_S2

Benign

0.84

.;T;T;D;T

M_CAP

Benign

0.0089

MetaRNN

Benign

0.19

T;T;T;T;T

MetaSVM

Benign

-0.97

MutationAssessor

Benign

0.79

N;N;.;.;.

PrimateAI

Uncertain

0.62

PROVEAN

Benign

-0.68

.;.;N;N;N

REVEL

Benign

0.10

Sift

Benign

0.16

.;.;T;T;T

Sift4G

Benign

0.13

.;.;T;T;T

Vest4

0.17, 0.22, 0.17

MVP

0.58

MPC

0.98

ClinPred

0.088

GERP RS

6.1

Varity_R

0.13

gMVP

0.18

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