dbSNP rs2644700: NXN:c.361-53731G>A (chr17-879809-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

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

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.14

Publications

4 publications found

Variant links:

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

NXN links:

ENSG00000262133 (HGNC:58546):

ENSG00000262133 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
NXN	NM_022463.5 link	c.361-53731G>A	intron_variant	Intron 1 of 7	ENST00000336868.8	NP_071908.2	Q6DKJ4-1
NXN	XM_005256756.5 link	c.361-53731G>A	intron_variant	Intron 1 of 6		XP_005256813.1
NXN	XM_005256758.4 link	c.21+17077G>A	intron_variant	Intron 1 of 7		XP_005256815.1
NXN	XM_017024949.2 link	c.361-53731G>A	intron_variant	Intron 1 of 5		XP_016880438.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NXN	ENST00000336868.8 link	c.361-53731G>A		intron_variant	Intron 1 of 7	1	NM_022463.5	ENSP00000337443.3		Q6DKJ4-1

Frequencies

GnomAD3 genomes

AF:

0.134

AC:

20417

AN:

151988

Hom.:

1954

Cov.:

show subpopulations

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:

AN:

Hom.:

AF XY:

0.0714

AC XY:

AN XY:

show subpopulations

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

African (AFR)

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AC:

AN:

South Asian (SAS)

AC:

AN:

European-Finnish (FIN)

AC:

AN:

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.167

AC:

AN:

Other (OTH)

AF:

0.00

AC:

AN:

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.038550), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.134

AC:

20434

AN:

152106

Hom.:

1953

Cov.:

AF XY:

0.135

AC XY:

10005

AN XY:

74364

show subpopulations

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:

AN:

294

European-Non Finnish (NFE)

AF:

0.0810

AC:

5509

AN:

67984

Other (OTH)

AF:

0.108

AC:

229

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

837

1674

2510

3347

4184

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

230

460

690

920

1150

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

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 v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.92

CADD

Benign

0.10

(source)

DANN

Benign

0.60

PhyloP100

-1.1

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over