chr3-49909069-C-T

Variant names:

• chr3-49909069-C-T
• rs2082843549
• NM_032355.4:c.1613G>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_032355.4(MON1A):​c.1613G>A​(p.Arg538His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000889 in 1,461,588 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000089 (0 hom.)
• Consequence: MON1A NM_032355.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.33
• 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.1613G>A	p.Arg538His	missense	Exon 6 of 6	NP_115731.3	Q86VX9-5
	MON1A	NM_001142501.2		c.1127G>A	p.Arg376His	missense	Exon 5 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.1613G>A	p.Arg538His	missense	Exon 6 of 6	ENSP00000296473.4	Q86VX9-5
	MON1A	ENST00000455683.7	TSL:1	c.1127G>A	p.Arg376His	missense	Exon 5 of 5	ENSP00000404793.3	Q86VX9-2
	MON1A	ENST00000864154.1		c.1724G>A	p.Arg575His	missense	Exon 7 of 7	ENSP00000534213.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000889 AC: 13 AN: 1461588 Hom.: 0 Cov.: 30 AF XY: 0.00000963 AC XY: 7 AN XY: 727058

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44682

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39690

South Asian (SAS) AF: 0.00 AC: 0 AN: 86226

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53356

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.0000108 AC: 12 AN: 1111894

Other (OTH) AF: 0.00 AC: 0 AN: 60374

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Benign	-0.048	T
BayesDel_noAF	Benign	-0.31
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.11	T
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.012	T
MetaRNN	Uncertain	0.54	D
MetaSVM	Benign	-0.38	T
MutationAssessor	Benign	1.5	L
PhyloP100		3.3
PrimateAI	Uncertain	0.57	T
PROVEAN	Uncertain	-2.8	D
REVEL	Benign	0.24
Sift	Uncertain	0.021	D
Sift4G	Uncertain	0.0070	D
Vest4		0.43
MutPred		0.62		Loss of MoRF binding (P = 0.0054)
MVP		0.63
MPC		1.9
ClinPred		0.98	D
GERP RS		4.5
Varity_R		0.12
gMVP		0.39
Mutation Taster		=69/31	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: rs2082843549; hg19: chr3-49946502; COSMIC: COSV56559611; COSMIC: COSV56559611;