10-70435399-C-T

Position:

chr10-70435399-C-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP3BP4BS2

The NM_018055.5(NODAL):c.778G>A(p.Gly260Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000706 in 1,614,028 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000073 ( 1 hom. )

Consequence

NODAL
NM_018055.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5U:5B:1

Conservation

PhyloP100: 5.73

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:

ENSG00000280401 (HGNC:):

ENSG00000280401 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

PP3

Multiple lines of computational evidence support a deleterious effect 9: AlphaMissense, BayesDel_noAF, Cadd, Dann, Eigen, M_CAP, MutationAssessor, PROVEAN, REVEL [when BayesDel_addAF, max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]

BP4

Computational evidence support a benign effect (MetaRNN=0.30680725).

BS2

High AC in GnomAd4 at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NODAL	NM_018055.5 linkuse as main transcript	c.778G>A	p.Gly260Arg	missense_variant	2/3	ENST00000287139.8	NP_060525.3	Q96S42
NODAL	NM_001329906.2 linkuse as main transcript	c.379G>A	p.Gly127Arg	missense_variant	2/3		NP_001316835.1
NODAL	XM_024448028.2 linkuse as main transcript	c.379G>A	p.Gly127Arg	missense_variant	2/3		XP_024303796.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
NODAL	ENST00000287139.8 linkuse as main transcript	c.778G>A	p.Gly260Arg	missense_variant	2/3	1	NM_018055.5	ENSP00000287139.3	Q96S42
NODAL	ENST00000414871.1 linkuse as main transcript	c.613G>A	p.Gly205Arg	missense_variant	2/3	1		ENSP00000394468.1	H7C0E4
ENSG00000280401	ENST00000624563.1 linkuse as main transcript	n.571C>T		non_coding_transcript_exon_variant	1/1	6

Frequencies

GnomAD3 genomes

AF:

0.0000526

AC:

AN:

152142

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000458

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000310

AC:

AN:

251458

Hom.:

AF XY:

0.000206

AC XY:

AN XY:

135912

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00220

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000725

AC:

106

AN:

1461886

Hom.:

Cov.:

AF XY:

0.0000591

AC XY:

AN XY:

727244

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00199

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000117

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.0000526

AC:

AN:

152142

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74342

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000458

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000168

Hom.:

Bravo

AF:

0.000155

ExAC

AF:

0.000346

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5Uncertain:5Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Heterotaxy, visceral, 5, autosomal

Pathogenic:2Uncertain:3Benign:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Juno Genomics, Hangzhou Juno Genomics, Inc	-	PM2_Supporting+PP3_Moderate+PS2_Supporting+PS4_Moderate+PP4 -
Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 01, 2009	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Dec 15, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genomic Medicine Lab, University of California San Francisco	Jan 07, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jan 20, 2021	The NODAL c.778G>A; p.Gly260Arg variant (rs121909283) is reported in the literature in multiple individuals affected with heterotaxy or cardiovascular malformations, although it has also been observed in healthy relatives and controls (Kingsmore 2019, Mohapatra 2009). This variant is found in the Latino population with an overall allele frequency of 0.22% (78/35440 alleles) in the Genome Aggregation Database. The glycine at codon 260 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.793). Functional studies suggest that the variant protein has mildly reduced transcriptional activation activity relative to wildtype NODAL, but the clinical relevance of these effects is unclear (Mohapatra 2009, Roessler 2009). Due to limited and conflicting information, the clinical significance of the p.Gly260Arg variant is uncertain at this time. References: Kingsmore et al. A Randomized, Controlled Trial of the Analytic and Diagnostic Performance of Singleton and Trio, Rapid Genome and Exome Sequencing in Ill Infants. Am J Hum Genet. 2019 Oct 3;105(4):719-733. Mohapatra B et al. Identification and functional characterization of NODAL rare variants in heterotaxy and isolated cardiovascular malformations. Hum Mol Genet. 2009 Mar 1;18(5):861-71. Roessler E et al. Cumulative ligand activity of NODAL mutations and modifiers are linked to human heart defects and holoprosencephaly. Mol Genet Metab. 2009 Sep-Oct;98(1-2):225-34. -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 13, 2023	- -

Wolff-Parkinson-White pattern

Pathogenic:1

Pathogenic, no assertion criteria provided

research

Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine

Jul 14, 2017

This variant was identified in an individual with Wolff-Parkinson-White syndrome -

Inborn genetic diseases

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 03, 2015

- -

Visceral heterotaxy

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego

Aug 29, 2017

This missense variant is predicted to lead to decreased NODAL activity. This variant was previously described in 8/82 Hispanic patients with heterotaxy syndrome and severe congenital heart disease. This variant has an autosomal dominant transmission with reduced penetrance and variable expressivity (PMID: 19064609). It has a very low allele frequency in gnomAD (0.000278) and is almost exclusively seen in the Hispanic population. Based on the combined evidence of the literature and potential functional effects of this missense variant, the p.Gly260Arg variant is classified as likely pathogenic. -

NODAL-related disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 31, 2023

The NODAL c.778G>A variant is predicted to result in the amino acid substitution p.Gly260Arg. In one study this variant was reported in eight Hispanic individuals with transposition of the great arteries (TGA); however, in one individual it was inherited from an unaffected parent and was found in one Hispanic control sample (Mohapatra et al. 2009. PubMed ID: 19064609) Additionally, it has been reported as inherited in an individual with TGA (Family 213 in Table S2/S15 - Clark et al. 2019. PubMed ID: 31019026). Functional studies found this variant retains ~80% of normal NODAL activity (Roessler et al. 2009. PubMed ID: 19553149). However, this variant has also been reported in 0.22% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/10-72195155-C-T) and has conflicting interpretations of pathogenicity in ClinVar ranging from likely benign to likely pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/8269/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Mar 16, 2023

Identified in multiple patients with complex congenital heart defects and heterotaxy or situs inversus referred for genetic testing at GeneDx and in published literature (Mohapatra et al., 2009; Hagen et al., 2016; Clark et al., 2019); Published functional studies about the effect of this variant on NODAL signaling are conflicting (Mohapatra et al., 2009; Roessler et al., 2009); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 19933292, 19553149, 22352765, 28738792, 27637763, 31019026, 31564432, 19064609) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.85

BayesDel_addAF

Benign

0.0057

BayesDel_noAF

Pathogenic

0.23

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.98

D;D

Eigen

Pathogenic

0.84

Eigen_PC

Pathogenic

0.75

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.95

D;D

M_CAP

Pathogenic

0.30

MetaRNN

Benign

0.31

T;T

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

2.9

M;.

PrimateAI

Uncertain

0.73

PROVEAN

Pathogenic

-7.3

D;D

REVEL

Pathogenic

0.79

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;.

Vest4

0.78

MutPred

0.75

Gain of MoRF binding (P = 0.0041);.;

MVP

0.89

MPC

1.2

ClinPred

0.41

GERP RS

5.0

Varity_R

0.85

gMVP

0.95

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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