rs104894169

chr10-70435629-C-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP6 BS2

The NM_018055.5(NODAL):c.548G>A(p.Arg183Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000632 in 1,613,932 control chromosomes in the GnomAD database, including 3 homozygotes. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R183W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00021 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000048 (3 hom.)
• Consequence: NODAL NM_018055.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1 B:1
• Conservation: PhyloP100: -1.36

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 Likely_benign. Variant got -5 ACMG points.

• BP6: Variant 10-70435629-C-T is Benign according to our data. Variant chr10-70435629-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 8268.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=1}.
• BS2: High AC in GnomAd at 32 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NODAL	NM_018055.5	c.548G>A	p.Arg183Gln	missense_variant	2/3	ENST00000287139.8
NODAL	NM_001329906.2	c.149G>A	p.Arg50Gln	missense_variant	2/3
NODAL	XM_024448028.2	c.149G>A	p.Arg50Gln	missense_variant	2/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NODAL	ENST00000287139.8	c.548G>A	p.Arg183Gln	missense_variant	2/3	1	NM_018055.5	P1
NODAL	ENST00000414871.1	c.383G>A	p.Arg128Gln	missense_variant	2/3	1
	ENST00000624563.1	n.801C>T		non_coding_transcript_exon_variant	1/1

Frequencies

GnomAD3 genomes AF: 0.000210 AC: 32 AN: 152140 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000748

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

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: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000878 AC: 22 AN: 250636 Hom.: 1 AF XY: 0.0000590 AC XY: 8 AN XY: 135562

Gnomad AFR exome AF: 0.000926

Gnomad AMR exome AF: 0.0000579

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: 0.0000265

Gnomad OTH exome AF: 0.000327

GnomAD4 exome AF: 0.0000479 AC: 70 AN: 1461674 Hom.: 3 Cov.: 29 AF XY: 0.0000440 AC XY: 32 AN XY: 727136

Gnomad4 AFR exome AF: 0.00122

Gnomad4 AMR exome AF: 0.0000447

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: 0.0000135

Gnomad4 OTH exome AF: 0.000116

GnomAD4 genome AF: 0.000210 AC: 32 AN: 152258 Hom.: 0 Cov.: 32 AF XY: 0.000201 AC XY: 15 AN XY: 74454

Gnomad4 AFR AF: 0.000746

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000158 Hom.: 0

Bravo AF: 0.000246

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000115 AC: 14

ClinVar

Significance: Conflicting classifications of pathogenicity

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

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Heterotaxy, visceral, 5, autosomal Pathogenic:1 Benign:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 01, 1997	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Nov 13, 2023	- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Jul 03, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.18
Cadd	Benign	0.059
Dann	Benign	0.79
DEOGEN2	Benign	0.40	T;T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.014	N
LIST_S2	Benign	0.61	T;T
M_CAP	Benign	0.049	D
MetaRNN	Uncertain	0.47	T;T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	0.95	L;.
MutationTaster	Benign	9.4e-12	A
PrimateAI	Benign	0.20	T
PROVEAN	Benign	-0.24	N;N
REVEL	Uncertain	0.50
Sift	Benign	0.61	T;T
Sift4G	Benign	0.71	T;T
Polyphen		0.0	B;.
Vest4		0.68
MVP		0.99
MPC		0.36
ClinPred		0.010	T
GERP RS		-8.3
Varity_R		0.019
gMVP		0.38

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs104894169; hg19: chr10-72195385; COSMIC: COSV99755325;