rs2231947

Variant names:

• chr10-70434098-G-A
• rs2231947
• NM_018055.5:c.892-1010C>T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

The NM_018055.5(NODAL):​c.892-1010C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.172 in 152,076 control chromosomes in the GnomAD database, including 2,422 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.17 (2422 hom., cov: 32)
• Consequence: NODAL NM_018055.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.251
• Publications: 6 publications found

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 Gene-Disease associations (from GenCC):

• heterotaxy, visceral, 5, autosomal

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
• situs inversus

  Inheritance: AD Classification: SUPPORTIVE, NO_KNOWN Submitted by: PanelApp Australia, Orphanet

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.195 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018055.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NODAL	NM_018055.5	MANE Select	c.892-1010C>T		intron	N/A	NP_060525.3
	NODAL	NM_001329906.2		c.493-1010C>T		intron	N/A	NP_001316835.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NODAL	ENST00000287139.8	TSL:1 MANE Select	c.892-1010C>T		intron	N/A	ENSP00000287139.3
	NODAL	ENST00000414871.1	TSL:1	c.727-1010C>T		intron	N/A	ENSP00000394468.1

Frequencies

GnomAD3 genomes AF: 0.172 AC: 26175 AN: 151956 Hom.: 2417 Cov.: 32

Gnomad AFR AF: 0.198

Gnomad AMI AF: 0.296

Gnomad AMR AF: 0.130

Gnomad ASJ AF: 0.242

Gnomad EAS AF: 0.0102

Gnomad SAS AF: 0.176

Gnomad FIN AF: 0.154

Gnomad MID AF: 0.171

Gnomad NFE AF: 0.175

Gnomad OTH AF: 0.176

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.172 AC: 26201 AN: 152076 Hom.: 2422 Cov.: 32 AF XY: 0.170 AC XY: 12610 AN XY: 74366

African (AFR) AF: 0.199 AC: 8232 AN: 41452

American (AMR) AF: 0.130 AC: 1990 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.242 AC: 840 AN: 3468

East Asian (EAS) AF: 0.0100 AC: 52 AN: 5182

South Asian (SAS) AF: 0.176 AC: 849 AN: 4816

European-Finnish (FIN) AF: 0.154 AC: 1631 AN: 10582

Middle Eastern (MID) AF: 0.173 AC: 51 AN: 294

European-Non Finnish (NFE) AF: 0.175 AC: 11916 AN: 67976

Other (OTH) AF: 0.175 AC: 370 AN: 2114

Alfa AF: 0.172 Hom.: 9117

Bravo AF: 0.170

Asia WGS AF: 0.115 AC: 398 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.61
DANN	Benign	0.36
PhyloP100		-0.25
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.49		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.49		Position offset: 2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs2231947; hg19: chr10-72193854;