3-49909069-C-T

Variant names:

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

Variant summary

Our verdict is Uncertain significance. Variant got 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

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]

ENSG00000228008 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MON1A	NM_032355.4	c.1613G>A	p.Arg538His	missense_variant	Exon 6 of 6	ENST00000296473.8	NP_115731.3
MON1A	NM_001142501.2	c.1127G>A	p.Arg376His	missense_variant	Exon 5 of 5		NP_001135973.2
MON1A	XM_006713345.5	c.1613G>A	p.Arg538His	missense_variant	Exon 6 of 6		XP_006713408.1
MON1A	XM_011534160.2	c.1613G>A	p.Arg538His	missense_variant	Exon 6 of 6		XP_011532462.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MON1A	ENST00000296473.8	c.1613G>A	p.Arg538His	missense_variant	Exon 6 of 6	1	NM_032355.4	ENSP00000296473.4

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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000108

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 16, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1904G>A (p.R635H) 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 1904, causing the arginine (R) at amino acid position 635 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	0.23
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;D;D;D
M_CAP	Benign	0.012	T
MetaRNN	Uncertain	0.54	D;D;D;D;D
MetaSVM	Benign	-0.38	T
MutationAssessor	Benign	1.5	L;L;.;.;.
PrimateAI	Uncertain	0.57	T
PROVEAN	Uncertain	-2.8	.;.;D;D;D
REVEL	Benign	0.24
Sift	Uncertain	0.021	.;.;D;D;D
Sift4G	Uncertain	0.0070	.;.;D;D;D
Vest4		0.43, 0.40, 0.30
MutPred		0.62		Loss of MoRF binding (P = 0.0054);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

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

Other links and lift over

dbSNP: rs2082843549; hg19: chr3-49946502; COSMIC: COSV56559611; COSMIC: COSV56559611;