dbSNP rs2279253: NODAL:c.*740T>C (chr10-70432196-A-G) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBA1

The NM_018055.5(NODAL):c.*740T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.463 in 152,928 control chromosomes in the GnomAD database, including 17,071 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.46 ( 16972 hom., cov: 34)

Exomes 𝑓: 0.49 ( 99 hom. )

Consequence

NODAL
NM_018055.5 3_prime_UTR

Scores

Clinical Significance

Benign criteria provided, single submitter B:2

Conservation

PhyloP100: 1.55

Publications

15 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
situs inversus
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

NODAL links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.57).

BP6

Variant 10-70432196-A-G is Benign according to our data. Variant chr10-70432196-A-G is described in ClinVar as Benign. ClinVar VariationId is 300288.Status of the report is criteria_provided_single_submitter, 1 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.702 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NODAL	NM_018055.5	MANE Select	c.*740T>C		3_prime_UTR	Exon 3 of 3	NP_060525.3
	NODAL	NM_001329906.2		c.*740T>C		3_prime_UTR	Exon 3 of 3	NP_001316835.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NODAL	ENST00000287139.8	TSL:1 MANE Select	c.*740T>C		3_prime_UTR	Exon 3 of 3	ENSP00000287139.3	Q96S42

Frequencies

GnomAD3 genomes

AF:

0.463

AC:

70400

AN:

151994

Hom.:

16960

Cov.:

show subpopulations

Gnomad AFR

AF:

0.357

Gnomad AMI

AF:

0.465

Gnomad AMR

AF:

0.473

Gnomad ASJ

AF:

0.413

Gnomad EAS

AF:

0.721

Gnomad SAS

AF:

0.496

Gnomad FIN

AF:

0.515

Gnomad MID

AF:

0.589

Gnomad NFE

AF:

0.497

Gnomad OTH

AF:

0.477

GnomAD4 exome

AF:

0.493

AC:

402

AN:

816

Hom.:

AF XY:

0.489

AC XY:

215

AN XY:

440

show subpopulations

African (AFR)

AF:

0.500

AC:

AN:

American (AMR)

AF:

0.468

AC:

AN:

124

Ashkenazi Jewish (ASJ)

AF:

0.250

AC:

AN:

East Asian (EAS)

AF:

0.500

AC:

AN:

South Asian (SAS)

AF:

0.500

AC:

AN:

European-Finnish (FIN)

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.500

AC:

319

AN:

638

Other (OTH)

AF:

0.450

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.512

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<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:

0.463

AC:

70435

AN:

152112

Hom.:

16972

Cov.:

AF XY:

0.467

AC XY:

34732

AN XY:

74364

show subpopulations

African (AFR)

AF:

0.356

AC:

14789

AN:

41498

American (AMR)

AF:

0.473

AC:

7234

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.413

AC:

1434

AN:

3468

East Asian (EAS)

AF:

0.721

AC:

3726

AN:

5168

South Asian (SAS)

AF:

0.496

AC:

2394

AN:

4828

European-Finnish (FIN)

AF:

0.515

AC:

5442

AN:

10572

Middle Eastern (MID)

AF:

0.595

AC:

175

AN:

294

European-Non Finnish (NFE)

AF:

0.497

AC:

33802

AN:

67972

Other (OTH)

AF:

0.481

AC:

1017

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.510

Heterozygous variant carriers

2021

4042

6062

8083

10104

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

658

1316

1974

2632

3290

<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:

0.488

Hom.:

71616

Bravo

AF:

0.454

Asia WGS

AF:

0.598

AC:

2078

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Heterotaxy, visceral, 5, autosomal (1)

Holoprosencephaly sequence (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.57

CADD

Benign

(source)

DANN

Benign

0.49

PhyloP100

1.6

Splicing

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over