rs150819707

Positions:

• chr10-70433076-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_018055.5(NODAL):​c.904C>T​(p.Arg302Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000919 in 1,613,944 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.00051 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00096 (0 hom.)
• Consequence: NODAL NM_018055.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:6 O:1
• Conservation: PhyloP100: 3.60

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]

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.059044242).
• BP6: Variant 10-70433076-G-A is Benign according to our data. Variant chr10-70433076-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 95883.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=6, Uncertain_significance=1, not_provided=1}.
• BS2: High AC in GnomAd4 at 77 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NODAL	NM_018055.5	c.904C>T	p.Arg302Cys	missense_variant	3/3	ENST00000287139.8	NP_060525.3
NODAL	NM_001329906.2	c.505C>T	p.Arg169Cys	missense_variant	3/3		NP_001316835.1
NODAL	XM_024448028.2	c.505C>T	p.Arg169Cys	missense_variant	3/3		XP_024303796.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NODAL	ENST00000287139.8	c.904C>T	p.Arg302Cys	missense_variant	3/3	1	NM_018055.5	ENSP00000287139.3
NODAL	ENST00000414871.1	c.739C>T	p.Arg247Cys	missense_variant	3/3	1		ENSP00000394468.1

Frequencies

GnomAD3 genomes AF: 0.000506 AC: 77 AN: 152024 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000970

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000557 AC: 140 AN: 251434 Hom.: 0 AF XY: 0.000486 AC XY: 66 AN XY: 135894

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.000231

Gnomad ASJ exome AF: 0.000992

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.000185

Gnomad NFE exome AF: 0.000914

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.000962 AC: 1406 AN: 1461802 Hom.: 0 Cov.: 31 AF XY: 0.000914 AC XY: 665 AN XY: 727204

Gnomad4 AFR exome AF: 0.000179

Gnomad4 AMR exome AF: 0.000268

Gnomad4 ASJ exome AF: 0.00187

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.000131

Gnomad4 NFE exome AF: 0.00114

Gnomad4 OTH exome AF: 0.000993

GnomAD4 genome AF: 0.000506 AC: 77 AN: 152142 Hom.: 0 Cov.: 32 AF XY: 0.000498 AC XY: 37 AN XY: 74364

Gnomad4 AFR AF: 0.000121

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000970

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00104 Hom.: 0

Bravo AF: 0.000570

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00105 AC: 9

ExAC AF: 0.000576 AC: 70

EpiCase AF: 0.00147

EpiControl AF: 0.000889

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:6 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Heterotaxy, visceral, 5, autosomal Benign:2 Other:1

not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 20, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

not provided Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 09, 2013	- -

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 03, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Holoprosencephaly sequence Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.35
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.24
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.75	D;D
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Benign	0.33	N
LIST_S2	Uncertain	0.96	D;D
M_CAP	Benign	0.041	D
MetaRNN	Benign	0.059	T;T
MetaSVM	Benign	-0.48	T
MutationAssessor	Benign	1.0	L;.
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-0.53	N;N
REVEL	Uncertain	0.30
Sift	Benign	0.091	T;T
Sift4G	Benign	0.17	T;T
Polyphen		1.0	D;.
Vest4		0.31
MVP		0.53
MPC		1.1
ClinPred		0.043	T
GERP RS		4.8
Varity_R		0.14
gMVP		0.86

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: rs150819707; hg19: chr10-72192832;