3-49910206-C-T

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

3
16

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]

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
MON1ANM_032355.4 linkc.1292G>A p.Arg431His missense_variant Exon 4 of 6 ENST00000296473.8 NP_115731.3 Q86VX9-5
MON1ANM_001142501.2 linkc.806G>A p.Arg269His missense_variant Exon 3 of 5 NP_001135973.2 Q86VX9-2
MON1AXM_006713345.5 linkc.1292G>A p.Arg431His missense_variant Exon 4 of 6 XP_006713408.1 Q86VX9-5
MON1AXM_011534160.2 linkc.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
MON1AENST00000296473.8 linkc.1292G>A p.Arg431His missense_variant Exon 4 of 6 1 NM_032355.4 ENSP00000296473.4 Q86VX9-5

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.00000797
AC:
2
AN:
250988
Hom.:
0
AF XY:
0.00000737
AC XY:
1
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:
23
AN:
1461766
Hom.:
0
Cov.:
31
AF XY:
0.0000124
AC XY:
9
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.:
32
Alfa
AF:
0.0000658
Hom.:
0
Bravo
AF:
0.00000756
TwinsUK
AF:
0.00
AC:
0
ALSPAC
AF:
0.000259
AC:
1
ESP6500AA
AF:
0.000227
AC:
1
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.0000165
AC:
2
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
T
BayesDel_noAF
Benign
-0.43
CADD
Benign
22
DANN
Uncertain
1.0
DEOGEN2
Benign
0.027
.;.;.;.;T
Eigen
Benign
-0.0091
Eigen_PC
Benign
0.16
FATHMM_MKL
Uncertain
0.87
D
LIST_S2
Benign
0.84
.;T;T;D;T
M_CAP
Benign
0.0089
T
MetaRNN
Benign
0.19
T;T;T;T;T
MetaSVM
Benign
-0.97
T
MutationAssessor
Benign
0.79
N;N;.;.;.
PrimateAI
Uncertain
0.62
T
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
T
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.

Other links and lift over

dbSNP: rs370695036; hg19: chr3-49947639; API