NM_018055.5:c.193+12C>T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: -0.129

Publications

10 publications found

Variant links:

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

NODAL links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId is 95881.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.603 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
NODAL	NM_018055.5 link	c.193+12C>T	intron_variant	Intron 1 of 2	ENST00000287139.8	NP_060525.3	Q96S42
NODAL	NM_001329906.2 link	c.-206-5480C>T	intron_variant	Intron 1 of 2		NP_001316835.1
NODAL	XM_024448028.2 link	c.-207+568C>T	intron_variant	Intron 1 of 2		XP_024303796.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NODAL	ENST00000287139.8 link	c.193+12C>T		intron_variant	Intron 1 of 2	1	NM_018055.5	ENSP00000287139.3		Q96S42
NODAL	ENST00000414871.1 link	c.29-5480C>T		intron_variant	Intron 1 of 2	1		ENSP00000394468.1		H7C0E4

Frequencies

GnomAD3 genomes

AF:

0.357

AC:

54291

AN:

152076

Hom.:

11438

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.399

AC:

67551

AN:

169238

AF XY:

0.396

show subpopulations

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 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.:

AF XY:

0.436

AC XY:

304700

AN XY:

699372

show subpopulations

African (AFR)

AF:

0.128

AC:

4139

AN:

32290

American (AMR)

AF:

0.374

AC:

14206

AN:

37988

Ashkenazi Jewish (ASJ)

AF:

0.309

AC:

7858

AN:

25408

East Asian (EAS)

AF:

0.558

AC:

20460

AN:

36656

South Asian (SAS)

AF:

0.272

AC:

21920

AN:

80734

European-Finnish (FIN)

AF:

0.432

AC:

19789

AN:

45804

Middle Eastern (MID)

AF:

0.380

AC:

2042

AN:

5374

European-Non Finnish (NFE)

AF:

0.465

AC:

506976

AN:

1090078

Other (OTH)

AF:

0.417

AC:

24447

AN:

58684

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

17996

35992

53988

71984

89980

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

15112

30224

45336

60448

75560

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.357

AC:

54291

AN:

152192

Hom.:

11442

Cov.:

AF XY:

0.357

AC XY:

26548

AN XY:

74400

show subpopulations

African (AFR)

AF:

0.140

AC:

5802

AN:

41562

American (AMR)

AF:

0.412

AC:

6310

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.307

AC:

1063

AN:

3468

East Asian (EAS)

AF:

0.621

AC:

3198

AN:

5150

South Asian (SAS)

AF:

0.277

AC:

1335

AN:

4826

European-Finnish (FIN)

AF:

0.420

AC:

4448

AN:

10598

Middle Eastern (MID)

AF:

0.490

AC:

144

AN:

294

European-Non Finnish (NFE)

AF:

0.453

AC:

30787

AN:

67972

Other (OTH)

AF:

0.378

AC:

798

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1704

3408

5113

6817

8521

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

520

1040

1560

2080

2600

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

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

LINK: link

Submissions by phenotype

not specified

Benign:5

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Mar 29, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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 -

May 17, 2016

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Heterotaxy, visceral, 5, autosomal

Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Sep 05, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Holoprosencephaly sequence

Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.77

CADD

Benign

3.1

(source)

DANN

Benign

0.95

PhyloP100

-0.13

PromoterAI

0.055

Neutral

(source)

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over