rs1904589

chr10-70435683-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -0.0130

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]

(HGNC:):

ACMG classification

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	UniProt
NODAL	NM_018055.5	c.494A>G	p.His165Arg	missense_variant	2/3	ENST00000287139.8
NODAL	NM_001329906.2	c.95A>G	p.His32Arg	missense_variant	2/3
NODAL	XM_024448028.2	c.95A>G	p.His32Arg	missense_variant	2/3

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.570 AC: 86568 AN: 151936 Hom.: 25388 Cov.: 32

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

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.: 82 AF XY: 0.586 AC XY: 425890 AN XY: 727172

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.: 32 AF XY: 0.576 AC XY: 42799 AN XY: 74328

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:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Heterotaxy, visceral, 5, autosomal Benign:4

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
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. -

not specified Benign:3

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 -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not provided Benign:2

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) -

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. -

NODAL-related disorder Benign:1

Benign, criteria provided, single submitter

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). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.72	T
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	N
LIST_S2	Benign	0.086	T;T
MetaRNN	Benign	7.6e-7	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.1	M;.
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.21	T
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	T
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

Other links and lift over

dbSNP: rs1904589; hg19: chr10-72195439; COSMIC: COSV54660789;