NM_018055.5:c.494A>G

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_018055.5(NODAL):c.494A>G(p.His165Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.583 in 1,613,808 control chromosomes in the GnomAD database, including 278,726 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H165Y) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.57 ( 25425 hom., cov: 32)

Exomes 𝑓: 0.58 ( 253301 hom. )

Consequence

NODAL
NM_018055.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: -0.0130

Publications

46 publications found

Variant links:

Genes affected

NODAL (HGNC:7865): (nodal growth differentiation factor) This gene encodes a secreted ligand of the TGF-beta (transforming growth factor-beta) superfamily of proteins. Ligands of this family bind various TGF-beta receptors leading to recruitment and activation of SMAD family transcription factors that regulate gene expression. The encoded preproprotein is proteolytically processed to generate the mature protein, which regulates early embryonic development. This protein is required for maintenance of human embryonic stem cell pluripotency and may play a role in human placental development. Mutations in this gene are associated with heterotaxy, a condition characterized by random orientation of visceral organs with respect to the left-right axis. [provided by RefSeq, Aug 2016]

NODAL Gene-Disease associations (from GenCC):

heterotaxy, visceral, 5, autosomal
Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
situs inversus
Inheritance: AD Classification: SUPPORTIVE, NO_KNOWN Submitted by: PanelApp Australia, Orphanet

NODAL links:

ENSG00000280401 (HGNC:):

ENSG00000280401 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=7.5708806E-7).

BP6

Variant 10-70435683-T-C is Benign according to our data. Variant chr10-70435683-T-C is described in ClinVar as Benign. ClinVar VariationId is 95882.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.932 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
NODAL	NM_018055.5 link	c.494A>G	p.His165Arg	missense_variant	Exon 2 of 3	ENST00000287139.8	NP_060525.3
NODAL	NM_001329906.2 link	c.95A>G	p.His32Arg	missense_variant	Exon 2 of 3		NP_001316835.1
NODAL	XM_024448028.2 link	c.95A>G	p.His32Arg	missense_variant	Exon 2 of 3		XP_024303796.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
NODAL	ENST00000287139.8 link	c.494A>G	p.His165Arg	missense_variant	Exon 2 of 3	1	NM_018055.5	ENSP00000287139.3
NODAL	ENST00000414871.1 link	c.329A>G	p.His110Arg	missense_variant	Exon 2 of 3	1		ENSP00000394468.1
ENSG00000280401	ENST00000624563.1 link	n.855T>C		non_coding_transcript_exon_variant	Exon 1 of 1	6

Frequencies

GnomAD3 genomes

AF:

0.570

AC:

86568

AN:

151936

Hom.:

25388

Cov.:

show subpopulations

Gnomad AFR

AF:

0.510

Gnomad AMI

AF:

0.522

Gnomad AMR

AF:

0.626

Gnomad ASJ

AF:

0.459

Gnomad EAS

AF:

0.954

Gnomad SAS

AF:

0.685

Gnomad FIN

AF:

0.593

Gnomad MID

AF:

0.633

Gnomad NFE

AF:

0.558

Gnomad OTH

AF:

0.573

GnomAD2 exomes

AF:

0.618

AC:

155053

AN:

250940

AF XY:

0.616

show subpopulations

Gnomad AFR exome

AF:

0.500

Gnomad AMR exome

AF:

0.677

Gnomad ASJ exome

AF:

0.460

Gnomad EAS exome

AF:

0.950

Gnomad FIN exome

AF:

0.590

Gnomad NFE exome

AF:

0.568

Gnomad OTH exome

AF:

0.599

GnomAD4 exome

AF:

0.584

AC:

853504

AN:

1461754

Hom.:

253301

Cov.:

AF XY:

0.586

AC XY:

425890

AN XY:

727172

show subpopulations

African (AFR)

AF:

0.508

AC:

17008

AN:

33480

American (AMR)

AF:

0.670

AC:

29943

AN:

44712

Ashkenazi Jewish (ASJ)

AF:

0.460

AC:

12022

AN:

26136

East Asian (EAS)

AF:

0.950

AC:

37700

AN:

39698

South Asian (SAS)

AF:

0.669

AC:

57703

AN:

86252

European-Finnish (FIN)

AF:

0.590

AC:

31490

AN:

53354

Middle Eastern (MID)

AF:

0.566

AC:

3262

AN:

5766

European-Non Finnish (NFE)

AF:

0.566

AC:

628999

AN:

1111968

Other (OTH)

AF:

0.586

AC:

35377

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

25731

51463

77194

102926

128657

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

17700

35400

53100

70800

88500

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.570

AC:

86643

AN:

152054

Hom.:

25425

Cov.:

AF XY:

0.576

AC XY:

42799

AN XY:

74328

show subpopulations

African (AFR)

AF:

0.510

AC:

21143

AN:

41472

American (AMR)

AF:

0.627

AC:

9575

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.459

AC:

1590

AN:

3464

East Asian (EAS)

AF:

0.954

AC:

4937

AN:

5174

South Asian (SAS)

AF:

0.685

AC:

3304

AN:

4820

European-Finnish (FIN)

AF:

0.593

AC:

6271

AN:

10578

Middle Eastern (MID)

AF:

0.639

AC:

188

AN:

294

European-Non Finnish (NFE)

AF:

0.558

AC:

37942

AN:

67950

Other (OTH)

AF:

0.577

AC:

1218

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.510

Heterozygous variant carriers

1913

3827

5740

7654

9567

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

750

1500

2250

3000

3750

<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:

0.571

Hom.:

100892

Bravo

AF:

0.569

TwinsUK

AF:

0.549

AC:

2035

ALSPAC

AF:

0.563

AC:

2171

ESP6500AA

AF:

0.506

AC:

2230

ESP6500EA

AF:

0.555

AC:

4775

ExAC

AF:

0.616

AC:

74820

Asia WGS

AF:

0.796

AC:

2770

AN:

3478

EpiCase

AF:

0.559

EpiControl

AF:

0.554

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Heterotaxy, visceral, 5, autosomal

Benign:4

Sep 05, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 29, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:3

Mar 29, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

Jul 03, 2013

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:3

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 25765999, 19553149) -

NODAL-related disorder

Benign:1

Apr 07, 2021

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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). -

Holoprosencephaly sequence

Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.083

BayesDel_addAF

Benign

-0.72

BayesDel_noAF

Benign

-0.66

CADD

Benign

1.7

(source)

DANN

Benign

0.34

DEOGEN2

Benign

0.38

T;T

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.047

LIST_S2

Benign

0.086

T;T

MetaRNN

Benign

7.6e-7

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.1

M;.

PhyloP100

-0.013

PrimateAI

Benign

0.21

PROVEAN

Benign

-0.39

N;N

REVEL

Benign

0.098

Sift

Benign

0.57

T;T

Sift4G

Benign

0.72

T;T

Polyphen

0.0

B;.

Vest4

0.0050

MPC

0.38

ClinPred

0.0041

GERP RS

-2.8

Varity_R

0.035

gMVP

0.18

Mutation Taster

=96/4

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

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over