NM_022463.5:c.361-53731G>A

Variant names:

• chr17-879809-C-T
• rs2644700
• NM_022463.5:c.361-53731G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_022463.5(NXN):​c.361-53731G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.134 in 152,126 control chromosomes in the GnomAD database, including 1,953 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.13 (1953 hom., cov: 32)
  • Exomes 𝑓: 0.10 (0 hom.)
• Consequence: NXN NM_022463.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.14
• Publications: 4 publications found

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]

NXN Gene-Disease associations (from GenCC):

• robinow syndrome, autosomal recessive 2

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• autosomal recessive Robinow syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000262133 (HGNC:58546):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.27 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_022463.5. 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
	NXN	NM_022463.5	MANE Select	c.361-53731G>A		intron	N/A	NP_071908.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NXN	ENST00000336868.8	TSL:1 MANE Select	c.361-53731G>A		intron	N/A	ENSP00000337443.3
	NXN	ENST00000575455.5	TSL:1	n.129+17077G>A		intron	N/A
	NXN	ENST00000571338.1	TSL:4	n.389+49854G>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.134 AC: 20417 AN: 151988 Hom.: 1954 Cov.: 32

Gnomad AFR AF: 0.262

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0876

Gnomad ASJ AF: 0.0997

Gnomad EAS AF: 0.0249

Gnomad SAS AF: 0.282

Gnomad FIN AF: 0.0612

Gnomad MID AF: 0.111

Gnomad NFE AF: 0.0810

Gnomad OTH AF: 0.110

GnomAD4 exome AF: 0.100 AC: 2 AN: 20 Hom.: 0 AF XY: 0.0714 AC XY: 1 AN XY: 14

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

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2

European-Non Finnish (NFE) AF: 0.167 AC: 2 AN: 12

Other (OTH) AF: 0.00 AC: 0 AN: 6

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0385499), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.134 AC: 20434 AN: 152106 Hom.: 1953 Cov.: 32 AF XY: 0.135 AC XY: 10005 AN XY: 74364

African (AFR) AF: 0.261 AC: 10844 AN: 41484

American (AMR) AF: 0.0875 AC: 1336 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.0997 AC: 346 AN: 3470

East Asian (EAS) AF: 0.0251 AC: 130 AN: 5174

South Asian (SAS) AF: 0.283 AC: 1360 AN: 4814

European-Finnish (FIN) AF: 0.0612 AC: 648 AN: 10594

Middle Eastern (MID) AF: 0.105 AC: 31 AN: 294

European-Non Finnish (NFE) AF: 0.0810 AC: 5509 AN: 67984

Other (OTH) AF: 0.108 AC: 229 AN: 2112

Alfa AF: 0.0915 Hom.: 1407

Bravo AF: 0.136

Asia WGS AF: 0.163 AC: 569 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.10
DANN	Benign	0.60
PhyloP100		-1.1
Mutation Taster		=100/0	polymorphism (auto)

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: rs2644700; hg19: chr17-783049;