NM_032355.4:c.1457G>C

Variant names:

• chr3-49909323-C-G
• rs778965655
• NM_032355.4:c.1457G>C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.10
• Publications: 0 publications found

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]

ENSG00000230698 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.865

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032355.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MON1A	NM_032355.4	MANE Select	c.1457G>C	p.Arg486Pro	missense	Exon 5 of 6	NP_115731.3	Q86VX9-5
	MON1A	NM_001142501.2		c.971G>C	p.Arg324Pro	missense	Exon 4 of 5	NP_001135973.2	Q86VX9-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MON1A	ENST00000296473.8	TSL:1 MANE Select	c.1457G>C	p.Arg486Pro	missense	Exon 5 of 6	ENSP00000296473.4	Q86VX9-5
	MON1A	ENST00000455683.7	TSL:1	c.971G>C	p.Arg324Pro	missense	Exon 4 of 5	ENSP00000404793.3	Q86VX9-2
	MON1A	ENST00000864154.1		c.1568G>C	p.Arg523Pro	missense	Exon 6 of 7	ENSP00000534213.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251312 AF XY: 0.00000736

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461760 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 727188

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53316

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111990

Other (OTH) AF: 0.00 AC: 0 AN: 60394

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.23
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.27	T
Eigen	Pathogenic	0.72
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.017	T
MetaRNN	Pathogenic	0.87	D
MetaSVM	Uncertain	-0.11	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		4.1
PrimateAI	Uncertain	0.62	T
PROVEAN	Pathogenic	-5.4	D
REVEL	Uncertain	0.33
Sift	Uncertain	0.012	D
Sift4G	Uncertain	0.0060	D
Vest4		0.82
MutPred		0.76		Loss of MoRF binding (P = 0.0152)
MVP		0.61
MPC		2.1
ClinPred		0.97	D
GERP RS		5.5
Varity_R		0.87
gMVP		0.85
Mutation Taster		=63/37	polymorphism

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

Other links and lift over

dbSNP: rs778965655; hg19: chr3-49946756;