rs2231947

Positions:

• chr10-70434098-G-A

Variant summary

Our verdict is Benign. Variant got -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

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 -8 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NODAL	NM_018055.5	c.892-1010C>T		intron_variant		ENST00000287139.8	NP_060525.3
NODAL	NM_001329906.2	c.493-1010C>T		intron_variant			NP_001316835.1
NODAL	XM_024448028.2	c.493-1010C>T		intron_variant			XP_024303796.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NODAL	ENST00000287139.8	c.892-1010C>T		intron_variant		1	NM_018055.5	ENSP00000287139.3
NODAL	ENST00000414871.1	c.727-1010C>T		intron_variant		1		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

Gnomad4 AFR AF: 0.199

Gnomad4 AMR AF: 0.130

Gnomad4 ASJ AF: 0.242

Gnomad4 EAS AF: 0.0100

Gnomad4 SAS AF: 0.176

Gnomad4 FIN AF: 0.154

Gnomad4 NFE AF: 0.175

Gnomad4 OTH AF: 0.175

Alfa AF: 0.174 Hom.: 3984

Bravo AF: 0.170

Asia WGS AF: 0.115 AC: 398 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.61
DANN	Benign	0.36

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

Publications

LitVar

Other links and lift over

dbSNP: rs2231947; hg19: chr10-72193854;