Genetic Variant NM_018055.5:c.*722G>C (chr10-70432214-C-G) – ACMG Classification: Benign (-20 pts)

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.*722G>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 0.44 in 153,198 control chromosomes in the GnomAD database, including 15,829 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.44 ( 15701 hom., cov: 34)

Exomes 𝑓: 0.50 ( 128 hom. )

Consequence

NODAL
NM_018055.5 3_prime_UTR

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 0.182

Publications

6 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.79).

BP6

Variant 10-70432214-C-G is Benign according to our data. Variant chr10-70432214-C-G is described in ClinVar as Benign. ClinVar VariationId is 300289.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.643 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.*722G>C		3_prime_UTR	Exon 3 of 3	NP_060525.3
	NODAL	NM_001329906.2		c.*722G>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.*722G>C		3_prime_UTR	Exon 3 of 3	ENSP00000287139.3	Q96S42

Frequencies

GnomAD3 genomes

AF:

0.439

AC:

66836

AN:

152078

Hom.:

15688

Cov.:

show subpopulations

Gnomad AFR

AF:

0.284

Gnomad AMI

AF:

0.465

Gnomad AMR

AF:

0.465

Gnomad ASJ

AF:

0.414

Gnomad EAS

AF:

0.662

Gnomad SAS

AF:

0.478

Gnomad FIN

AF:

0.515

Gnomad MID

AF:

0.585

Gnomad NFE

AF:

0.497

Gnomad OTH

AF:

0.457

GnomAD4 exome

AF:

0.503

AC:

504

AN:

1002

Hom.:

128

AF XY:

0.487

AC XY:

255

AN XY:

524

show subpopulations

African (AFR)

AF:

0.500

AC:

AN:

American (AMR)

AF:

0.445

AC:

AN:

182

Ashkenazi Jewish (ASJ)

AF:

0.250

AC:

AN:

East Asian (EAS)

AF:

0.571

AC:

AN:

South Asian (SAS)

AF:

0.500

AC:

AN:

European-Finnish (FIN)

AF:

0.500

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.518

AC:

380

AN:

734

Other (OTH)

AF:

0.500

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.526

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:

0.439

AC:

66845

AN:

152196

Hom.:

15701

Cov.:

AF XY:

0.443

AC XY:

32972

AN XY:

74416

show subpopulations

African (AFR)

AF:

0.283

AC:

11766

AN:

41524

American (AMR)

AF:

0.465

AC:

7105

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.414

AC:

1434

AN:

3466

East Asian (EAS)

AF:

0.661

AC:

3422

AN:

5174

South Asian (SAS)

AF:

0.478

AC:

2310

AN:

4830

European-Finnish (FIN)

AF:

0.515

AC:

5449

AN:

10588

Middle Eastern (MID)

AF:

0.592

AC:

174

AN:

294

European-Non Finnish (NFE)

AF:

0.497

AC:

33785

AN:

67998

Other (OTH)

AF:

0.462

AC:

977

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.510

Heterozygous variant carriers

1939

3878

5816

7755

9694

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

630

1260

1890

2520

3150

<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:

0.321

Hom.:

890

Bravo

AF:

0.427

Asia WGS

AF:

0.549

AC:

1910

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Heterotaxy, visceral, 5, autosomal (1)

Holoprosencephaly sequence (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.79

CADD

Benign

5.8

(source)

DANN

Benign

0.53

PhyloP100

0.18

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