17-803674-G-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_022463.5(NXN):c.1125+8C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000937 in 1,614,034 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0039 (6 hom., cov: 33)
  • Exomes 𝑓: 0.00063 (5 hom.)
• Consequence: NXN NM_022463.5 splice_region, intron
• Scores: Splicing: ADA: 0.00007095
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.634

Genes affected

NXN (HGNC:18008): (nucleoredoxin) This gene encodes a member of the thioredoxin superfamily, a group of small, multifunctional redox-active proteins. Members of this family are characterized by a conserved active motif called the thioredoxin fold that catalyzes disulfide bond formation and isomerization. The encoded protein acts a redox-dependent regulator of the Wnt signaling pathway and is involved in cell growth and differentiation. [provided by RefSeq, Sep 2015]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 17-803674-G-A is Benign according to our data. Variant chr17-803674-G-A is described in ClinVar as [Benign]. Clinvar id is 787988.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NXN	NM_022463.5	c.1125+8C>T		splice_region_variant, intron_variant		ENST00000336868.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NXN	ENST00000336868.8	c.1125+8C>T		splice_region_variant, intron_variant		1	NM_022463.5	P1

Frequencies

GnomAD3 genomes AF: 0.00385 AC: 586 AN: 152168 Hom.: 6 Cov.: 33

Gnomad AFR AF: 0.0130

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00242

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.000957

GnomAD3 exomes AF: 0.00134 AC: 338 AN: 251320 Hom.: 1 AF XY: 0.000935 AC XY: 127 AN XY: 135840

Gnomad AFR exome AF: 0.0161

Gnomad AMR exome AF: 0.000810

Gnomad ASJ exome AF: 0.00139

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000229

Gnomad OTH exome AF: 0.00130

GnomAD4 exome AF: 0.000631 AC: 922 AN: 1461748 Hom.: 5 Cov.: 32 AF XY: 0.000539 AC XY: 392 AN XY: 727192

Gnomad4 AFR exome AF: 0.0157

Gnomad4 AMR exome AF: 0.000917

Gnomad4 ASJ exome AF: 0.00111

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000696

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000190

Gnomad4 OTH exome AF: 0.00149

GnomAD4 genome AF: 0.00387 AC: 590 AN: 152286 Hom.: 6 Cov.: 33 AF XY: 0.00360 AC XY: 268 AN XY: 74462

Gnomad4 AFR AF: 0.0130

Gnomad4 AMR AF: 0.00242

Gnomad4 ASJ AF: 0.000865

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.000947

Alfa AF: 0.00228 Hom.: 0

Bravo AF: 0.00505

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.000296

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 17, 2023

- -

NXN-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 12, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
Cadd	Benign	0.69
Dann	Benign	0.36
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000071
dbscSNV1_RF	Benign	0.0040
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: rs115282889; hg19: chr17-706914;