rs10999338

Positions:

• chr10-70441463-G-A
• chr10-70441463-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_018055.5(NODAL):​c.193+12C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.432 in 1,565,208 control chromosomes in the GnomAD database, including 152,519 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.36 (11442 hom., cov: 34)
  • Exomes 𝑓: 0.44 (141077 hom.)
• Consequence: NODAL NM_018055.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -0.129

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 10-70441463-G-A is Benign according to our data. Variant chr10-70441463-G-A is described in ClinVar as [Benign]. Clinvar id is 95881.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-70441463-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.603 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NODAL	NM_018055.5	c.193+12C>T		intron_variant		ENST00000287139.8	NP_060525.3
NODAL	NM_001329906.2	c.-206-5480C>T		intron_variant			NP_001316835.1
NODAL	XM_024448028.2	c.-207+568C>T		intron_variant			XP_024303796.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NODAL	ENST00000287139.8	c.193+12C>T		intron_variant		1	NM_018055.5	ENSP00000287139	P1
NODAL	ENST00000414871.1	c.29-5480C>T		intron_variant		1		ENSP00000394468

Frequencies

GnomAD3 genomes AF: 0.357 AC: 54291 AN: 152076 Hom.: 11438 Cov.: 34

Gnomad AFR AF: 0.140

Gnomad AMI AF: 0.446

Gnomad AMR AF: 0.412

Gnomad ASJ AF: 0.307

Gnomad EAS AF: 0.622

Gnomad SAS AF: 0.276

Gnomad FIN AF: 0.420

Gnomad MID AF: 0.478

Gnomad NFE AF: 0.453

Gnomad OTH AF: 0.376

GnomAD3 exomes AF: 0.399 AC: 67551 AN: 169238 Hom.: 14503 AF XY: 0.396 AC XY: 36596 AN XY: 92298

Gnomad AFR exome AF: 0.131

Gnomad AMR exome AF: 0.371

Gnomad ASJ exome AF: 0.312

Gnomad EAS exome AF: 0.636

Gnomad SAS exome AF: 0.269

Gnomad FIN exome AF: 0.426

Gnomad NFE exome AF: 0.455

Gnomad OTH exome AF: 0.409

GnomAD4 exome AF: 0.440 AC: 621837 AN: 1413016 Hom.: 141077 Cov.: 42 AF XY: 0.436 AC XY: 304700 AN XY: 699372

Gnomad4 AFR exome AF: 0.128

Gnomad4 AMR exome AF: 0.374

Gnomad4 ASJ exome AF: 0.309

Gnomad4 EAS exome AF: 0.558

Gnomad4 SAS exome AF: 0.272

Gnomad4 FIN exome AF: 0.432

Gnomad4 NFE exome AF: 0.465

Gnomad4 OTH exome AF: 0.417

GnomAD4 genome AF: 0.357 AC: 54291 AN: 152192 Hom.: 11442 Cov.: 34 AF XY: 0.357 AC XY: 26548 AN XY: 74400

Gnomad4 AFR AF: 0.140

Gnomad4 AMR AF: 0.412

Gnomad4 ASJ AF: 0.307

Gnomad4 EAS AF: 0.621

Gnomad4 SAS AF: 0.277

Gnomad4 FIN AF: 0.420

Gnomad4 NFE AF: 0.453

Gnomad4 OTH AF: 0.378

Alfa AF: 0.381 Hom.: 2204

Bravo AF: 0.348

Asia WGS AF: 0.389 AC: 1353 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 29, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 17, 2016	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Heterotaxy, visceral, 5, autosomal Benign:3

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

Holoprosencephaly sequence Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	3.1
DANN	Benign	0.95

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: rs10999338; hg19: chr10-72201219; COSMIC: COSV54660797; COSMIC: COSV54660797;