Genetic Variant MON1A:p.Val530Ile (chr3-49909094-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_032355.4(MON1A):c.1588G>A(p.Val530Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000233 in 1,461,378 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.000023 ( 0 hom. )

Consequence

MON1A
NM_032355.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.194

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 Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.058364213).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MON1A	NM_032355.4 link	c.1588G>A	p.Val530Ile	missense_variant	Exon 6 of 6	ENST00000296473.8	NP_115731.3	Q86VX9-5
MON1A	NM_001142501.2 link	c.1102G>A	p.Val368Ile	missense_variant	Exon 5 of 5		NP_001135973.2	Q86VX9-2
MON1A	XM_006713345.5 link	c.1588G>A	p.Val530Ile	missense_variant	Exon 6 of 6		XP_006713408.1	Q86VX9-5
MON1A	XM_011534160.2 link	c.1588G>A	p.Val530Ile	missense_variant	Exon 6 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.1588G>A	p.Val530Ile	missense_variant	Exon 6 of 6	1	NM_032355.4	ENSP00000296473.4		Q86VX9-5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000159

AC:

AN:

250812

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135634

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:

0.0000353

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000233

AC:

AN:

1461378

Hom.:

Cov.:

AF XY:

0.0000220

AC XY:

AN XY:

726912

show subpopulations

Gnomad4 AFR exome

AF:

0.000149

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:

0.0000252

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000756

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

Dec 03, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1879G>A (p.V627I) alteration is located in exon 6 (coding exon 6) of the MON1A gene. This alteration results from a G to A substitution at nucleotide position 1879, causing the valine (V) at amino acid position 627 to be replaced by an isoleucine (I). 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

0.082

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.60

CADD

Benign

DANN

Benign

0.84

DEOGEN2

Benign

0.0028

.;.;.;.;T

Eigen

Benign

-0.86

Eigen_PC

Benign

-0.66

FATHMM_MKL

Benign

0.12

LIST_S2

Benign

0.75

.;T;T;T;T

M_CAP

Benign

0.0012

MetaRNN

Benign

0.058

T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.10

N;N;.;.;.

PrimateAI

Benign

0.37

PROVEAN

Benign

0.53

.;.;N;N;N

REVEL

Benign

0.096

Sift

Benign

1.0

.;.;T;T;T

Sift4G

Benign

1.0

.;.;T;T;T

Vest4

0.065, 0.040, 0.035

MutPred

0.55

Loss of glycosylation at S531 (P = 0.0391);Loss of glycosylation at S531 (P = 0.0391);.;.;.;

MVP

0.46

MPC

0.64

ClinPred

0.56

GERP RS

3.2

Varity_R

0.022

gMVP

0.26

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