20-4177528-G-C

Variant names:

• chr20-4177528-G-C
• rs370515510
• NM_175839.3:c.386G>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_175839.3(SMOX):​c.386G>C​(p.Arg129Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000692 in 1,444,626 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign 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. R129H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: SMOX NM_175839.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.55
• Publications: 3 publications found

Genes affected

SMOX (HGNC:15862): (spermine oxidase) Polyamines are ubiquitous polycationic alkylamines which include spermine, spermidine, putrescine, and agmatine. These molecules participate in a broad range of cellular functions which include cell cycle modulation, scavenging reactive oxygen species, and the control of gene expression. These molecules also play important roles in neurotransmission through their regulation of cell-surface receptor activity, involvement in intracellular signalling pathways, and their putative roles as neurotransmitters. This gene encodes an FAD-containing enzyme that catalyzes the oxidation of spermine to spermadine and secondarily produces hydrogen peroxide. Multiple transcript variants encoding different isoenzymes have been identified for this gene, some of which have failed to demonstrate significant oxidase activity on natural polyamine substrates. The characterized isoenzymes have distinctive biochemical characteristics and substrate specificities, suggesting the existence of additional levels of complexity in polyamine catabolism. [provided by RefSeq, Jul 2012]

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.27345997).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_175839.3. 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
	SMOX	NM_175839.3	MANE Select	c.386G>C	p.Arg129Pro	missense	Exon 3 of 7	NP_787033.1	Q9NWM0-1
	SMOX	NM_001270691.2		c.386G>C	p.Arg129Pro	missense	Exon 3 of 8	NP_001257620.1	Q9NWM0-6
	SMOX	NM_175842.3		c.386G>C	p.Arg129Pro	missense	Exon 3 of 9	NP_787036.1	Q9NWM0-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMOX	ENST00000305958.9	TSL:1 MANE Select	c.386G>C	p.Arg129Pro	missense	Exon 3 of 7	ENSP00000307252.4	Q9NWM0-1
	SMOX	ENST00000621355.4	TSL:1	c.386G>C	p.Arg129Pro	missense	Exon 3 of 8	ENSP00000478305.1	Q9NWM0-6
	SMOX	ENST00000278795.7	TSL:1	c.386G>C	p.Arg129Pro	missense	Exon 3 of 9	ENSP00000278795.3	Q9NWM0-4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000448 AC: 1 AN: 223268 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000316

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: 6.92e-7 AC: 1 AN: 1444626 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 716692

African (AFR) AF: 0.00 AC: 0 AN: 33328

American (AMR) AF: 0.0000236 AC: 1 AN: 42314

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25794

East Asian (EAS) AF: 0.00 AC: 0 AN: 39264

South Asian (SAS) AF: 0.00 AC: 0 AN: 83342

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52200

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5754

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1102902

Other (OTH) AF: 0.00 AC: 0 AN: 59728

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.71
BayesDel_addAF	Benign	-0.0021	T
BayesDel_noAF	Benign	-0.14
CADD	Benign	20
DANN	Uncertain	0.97
DEOGEN2	Pathogenic	0.83	D
Eigen	Benign	-0.59
Eigen_PC	Benign	-0.53
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Uncertain	0.95	D
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.27	T
MetaSVM	Benign	-0.40	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		1.6
PrimateAI	Benign	0.22	T
PROVEAN	Uncertain	-3.3	D
REVEL	Uncertain	0.30
Sift	Benign	0.13	T
Sift4G	Benign	0.20	T
Polyphen		0.18	B
Vest4		0.44
MutPred		0.50		Loss of MoRF binding (P = 0.0441)
MVP		0.34
MPC		1.2
ClinPred		0.55	D
GERP RS		-2.3
PromoterAI		-0.015	Neutral
Varity_R		0.44
gMVP		0.90
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: rs370515510; hg19: chr20-4158175;