dbSNP rs778965655: MON1A:p.Arg486Pro (chr3-49909323-C-G) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_032355.4(MON1A):c.1457G>C(p.Arg486Pro) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,760 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. R486H) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

MON1A
NM_032355.4 missense

Scores

Clinical Significance

Not reported in ClinVar

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:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.865

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MON1A	NM_032355.4 link	c.1457G>C	p.Arg486Pro	missense_variant	Exon 5 of 6	ENST00000296473.8	NP_115731.3	Q86VX9-5
MON1A	NM_001142501.2 link	c.971G>C	p.Arg324Pro	missense_variant	Exon 4 of 5		NP_001135973.2	Q86VX9-2
MON1A	XM_006713345.5 link	c.1457G>C	p.Arg486Pro	missense_variant	Exon 5 of 6		XP_006713408.1	Q86VX9-5
MON1A	XM_011534160.2 link	c.1457G>C	p.Arg486Pro	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>C	p.Arg486Pro	missense_variant	Exon 5 of 6	1	NM_032355.4	ENSP00000296473.4		Q86VX9-5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251312

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135874

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:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461760

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727188

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.26

BayesDel_noAF

Pathogenic

0.23

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.27

.;.;.;.;T

Eigen

Pathogenic

0.72

Eigen_PC

Pathogenic

0.69

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.89

.;D;D;D;D

M_CAP

Benign

0.017

MetaRNN

Pathogenic

0.87

D;D;D;D;D

MetaSVM

Uncertain

-0.11

MutationAssessor

Uncertain

2.5

M;M;.;.;.

PrimateAI

Uncertain

0.62

PROVEAN

Pathogenic

-5.4

.;.;D;D;D

REVEL

Uncertain

0.33

Sift

Uncertain

0.012

.;.;D;D;D

Sift4G

Uncertain

0.0060

.;.;D;D;D

Vest4

0.82, 0.82, 0.83

MutPred

0.76

Loss of MoRF binding (P = 0.0152);Loss of MoRF binding (P = 0.0152);.;.;.;

MVP

0.61

MPC

2.1

ClinPred

0.97

GERP RS

5.5

Varity_R

0.87

gMVP

0.85

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

Computational scores

Splicing

Publications

LitVar

Other links and lift over