13-43298357-C-T

Variant names:

• chr13-43298357-C-T
• rs138978304
• NM_001347969.2:c.1435G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001347969.2(ENOX1):​c.1435G>A​(p.Gly479Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000665 in 150,396 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict 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. G479R) has been classified as Uncertain significance.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
• Consequence: ENOX1 NM_001347969.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.82
• Publications: 4 publications found

Genes affected

ENOX1 (HGNC:25474): (ecto-NOX disulfide-thiol exchanger 1) The protein encoded by this gene is involved in plasma membrane electron transport pathways. The encoded protein has both a hydroquinone (NADH) oxidase activity and a protein disulfide-thiol interchange activity. The two activities cycle with a periodicity of 24 minutes, with one activity being at its peak when the other is at its lowest. [provided by RefSeq, Dec 2016]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.085354835).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001347969.2. 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
	ENOX1	NM_001347969.2	MANE Select	c.1435G>A	p.Gly479Ser	missense	Exon 12 of 17	NP_001334898.1	A0A024RDT8
	ENOX1	NM_001347963.2		c.1540G>A	p.Gly514Ser	missense	Exon 11 of 16	NP_001334892.1
	ENOX1	NM_001127615.3		c.1435G>A	p.Gly479Ser	missense	Exon 12 of 17	NP_001121087.1	A0A024RDT8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ENOX1	ENST00000690772.1	MANE Select	c.1435G>A	p.Gly479Ser	missense	Exon 12 of 17	ENSP00000509229.1	Q8TC92-1
	ENOX1	ENST00000261488.10	TSL:1	c.1435G>A	p.Gly479Ser	missense	Exon 12 of 17	ENSP00000261488.6	Q8TC92-1
	ENOX1	ENST00000871211.1		c.1435G>A	p.Gly479Ser	missense	Exon 13 of 18	ENSP00000541270.1

Frequencies

GnomAD3 genomes AF: 0.00000665 AC: 1 AN: 150396 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000663

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 35

GnomAD4 genome AF: 0.00000665 AC: 1 AN: 150396 Hom.: 0 Cov.: 33 AF XY: 0.0000137 AC XY: 1 AN XY: 73240

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

African (AFR) AF: 0.00 AC: 0 AN: 41078

American (AMR) AF: 0.0000663 AC: 1 AN: 15090

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5166

South Asian (SAS) AF: 0.00 AC: 0 AN: 4790

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9754

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 308

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67772

Other (OTH) AF: 0.00 AC: 0 AN: 2058

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.048	T
Eigen	Benign	-0.095
Eigen_PC	Benign	0.089
FATHMM_MKL	Benign	0.73	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.0089	T
MetaRNN	Benign	0.085	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	L
PhyloP100		1.8
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-2.2	N
REVEL	Benign	0.036
Sift	Benign	0.11	T
Sift4G	Benign	0.29	T
Polyphen		0.0040	B
Vest4		0.18
MutPred		0.27		Gain of relative solvent accessibility (P = 0.1259)
MVP		0.31
MPC		0.56
ClinPred		0.85	D
GERP RS		4.9
Varity_R		0.18
gMVP		0.13
Mutation Taster		=97/3	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: rs138978304; hg19: chr13-43872493;