rs1904589

Positions:

chr10-70435683-T-C

Variant summary

Our verdict is Benign. Variant got -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. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as 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

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 links:

(HGNC:):

links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 id is 95882.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-70435683-T-C is described in Lovd as [Benign]. Variant chr10-70435683-T-C is described in Lovd as [Likely_benign].

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/exons	MANE	Protein
NODAL	NM_018055.5 linkuse as main transcript	c.494A>G	p.His165Arg	missense_variant	2/3	ENST00000287139.8	NP_060525.3
NODAL	NM_001329906.2 linkuse as main transcript	c.95A>G	p.His32Arg	missense_variant	2/3		NP_001316835.1
NODAL	XM_024448028.2 linkuse as main transcript	c.95A>G	p.His32Arg	missense_variant	2/3		XP_024303796.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
NODAL	ENST00000287139.8 linkuse as main transcript	c.494A>G	p.His165Arg	missense_variant	2/3	1	NM_018055.5	ENSP00000287139	P1
NODAL	ENST00000414871.1 linkuse as main transcript	c.329A>G	p.His110Arg	missense_variant	2/3	1		ENSP00000394468
	ENST00000624563.1 linkuse as main transcript	n.855T>C		non_coding_transcript_exon_variant	1/1

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

GnomAD3 exomes

AF:

0.618

AC:

155053

AN:

250940

Hom.:

49561

AF XY:

0.616

AC XY:

83559

AN XY:

135670

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 SAS exome

AF:

0.676

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

Gnomad4 AFR exome

AF:

0.508

Gnomad4 AMR exome

AF:

0.670

Gnomad4 ASJ exome

AF:

0.460

Gnomad4 EAS exome

AF:

0.950

Gnomad4 SAS exome

AF:

0.669

Gnomad4 FIN exome

AF:

0.590

Gnomad4 NFE exome

AF:

0.566

Gnomad4 OTH exome

AF:

0.586

GnomAD4 genome

AF:

0.570

AC:

86643

AN:

152054

Hom.:

25425

Cov.:

AF XY:

0.576

AC XY:

42799

AN XY:

74328

show subpopulations

Gnomad4 AFR

AF:

0.510

Gnomad4 AMR

AF:

0.627

Gnomad4 ASJ

AF:

0.459

Gnomad4 EAS

AF:

0.954

Gnomad4 SAS

AF:

0.685

Gnomad4 FIN

AF:

0.593

Gnomad4 NFE

AF:

0.558

Gnomad4 OTH

AF:

0.577

Alfa

AF:

0.568

Hom.:

51792

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

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

not specified

Benign:3

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 03, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 29, 2016	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 -

not provided

Benign:3

Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 25765999, 19553149) -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

NODAL-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 07, 2021

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

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

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. -

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

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;.

MutationTaster

Benign

1.0

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over