1-156591968-C-T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 4P and 5B. PM1 PM2 BP4_Strong BS1_Supporting

The NM_144772.3(NAXE):c.164C>T(p.Thr55Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000769 in 1,613,088 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. T55T) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 34)
  • Exomes 𝑓: 0.000081 (0 hom.)
• Consequence: NAXE NM_144772.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0600

Genes affected

NAXE (HGNC:18453): (NAD(P)HX epimerase) The product of this gene interacts with apolipoprotein A-I (apoA-I), the major apolipoprotein of high-density lipoproteins (HDLs). It is secreted into some bodily fluids, and its synthesis and secretion are stimulated in vitro by incubating cells with apoA-I. The human genome contains related pseudogenes. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_benign. Variant got -1 ACMG points.

• PM1: In a chain NAD(P)H-hydrate epimerase (size 240) in uniprot entity NNRE_HUMAN there are 9 pathogenic changes around while only 3 benign (75%) in NM_144772.3
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.026380658).
• BS1: Variant frequency is greater than expected in population sas. gnomad4_exome allele frequency = 0.0000815 (119/1460928) while in subpopulation SAS AF= 0.000615 (53/86246). AF 95% confidence interval is 0.000482. There are 0 homozygotes in gnomad4_exome. There are 70 alleles in male gnomad4_exome subpopulation. Median coverage is 83. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NAXE	NM_144772.3	c.164C>T	p.Thr55Met	missense_variant	1/6	ENST00000368235.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NAXE	ENST00000368235.8	c.164C>T	p.Thr55Met	missense_variant	1/6	1	NM_144772.3	P1

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152160 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000830

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000110 AC: 27 AN: 246108 Hom.: 0 AF XY: 0.000127 AC XY: 17 AN XY: 134120

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 SAS exome AF: 0.000817

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000182

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000815 AC: 119 AN: 1460928 Hom.: 0 Cov.: 83 AF XY: 0.0000963 AC XY: 70 AN XY: 726812

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: 0.000615

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000549

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 152160 Hom.: 0 Cov.: 34 AF XY: 0.0000404 AC XY: 3 AN XY: 74332

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000830

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ExAC AF: 0.0000990 AC: 12

EpiCase AF: 0.000273

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jul 17, 2023

This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 55 of the NAXE protein (p.Thr55Met). This variant is present in population databases (no rsID available, gnomAD 0.08%). This variant has not been reported in the literature in individuals affected with NAXE-related conditions. ClinVar contains an entry for this variant (Variation ID: 2143271). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.61
Cadd	Benign	19
Dann	Uncertain	0.98
Eigen	Benign	-0.77
Eigen_PC	Benign	-0.77
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.75	T;T;T
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.026	T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-0.53	N;N;N
REVEL	Benign	0.074
Sift	Benign	0.047	D;T;T
Sift4G	Benign	0.071	T;T;D
Polyphen		0.99	D;B;D
Vest4		0.21
MutPred		0.39		Gain of catalytic residue at V51 (P = 0.038);Gain of catalytic residue at V51 (P = 0.038);Gain of catalytic residue at V51 (P = 0.038);
MVP		0.14
MPC		0.47
ClinPred		0.54	D
GERP RS		0.95
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.037
gMVP		0.63

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: rs1553232337; hg19: chr1-156561760;