3-16301856-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_138381.5(OXNAD1):c.663A>T(p.Glu221Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,490 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: OXNAD1 NM_138381.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.692

Genes affected

OXNAD1 (HGNC:25128): (oxidoreductase NAD binding domain containing 1) Predicted to enable oxidoreductase activity. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.37827516).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OXNAD1	NM_138381.5	c.663A>T	p.Glu221Asp	missense_variant	7/9	ENST00000285083.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OXNAD1	ENST00000285083.10	c.663A>T	p.Glu221Asp	missense_variant	7/9	1	NM_138381.5	P3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000399 AC: 1 AN: 250664 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135490

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS 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: 0.00000137 AC: 2 AN: 1461490 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 726994

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 13, 2021

The c.663A>T (p.E221D) alteration is located in exon 7 (coding exon 5) of the OXNAD1 gene. This alteration results from a A to T substitution at nucleotide position 663, causing the glutamic acid (E) at amino acid position 221 to be replaced by an aspartic acid (D). 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	Uncertain	0.53
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Pathogenic	0.17
Cadd	Benign	18
Dann	Uncertain	1.0
DEOGEN2	Benign	0.32	T;T;T;T;.
Eigen	Benign	-0.39
Eigen_PC	Benign	-0.56
FATHMM_MKL	Benign	0.55	D
LIST_S2	Uncertain	0.94	D;.;D;.;D
M_CAP	Uncertain	0.096	D
MetaRNN	Benign	0.38	T;T;T;T;T
MetaSVM	Uncertain	-0.010	T
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.54	T
Sift4G	Benign	0.082	T;T;T;T;T
Polyphen		1.0	.;D;D;.;.
Vest4		0.35
MutPred		0.68		.;Loss of methylation at K225 (P = 0.112);Loss of methylation at K225 (P = 0.112);.;Loss of methylation at K225 (P = 0.112);
MVP		0.39
MPC		0.14
ClinPred		0.87	D
GERP RS		-5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.24
gMVP		0.90

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: rs376034689; hg19: chr3-16343363;