10-70432457-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBS1BS2

The NM_018055.5(NODAL):c.*479C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00807 in 197,568 control chromosomes in the GnomAD database, including 24 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.010 ( 23 hom., cov: 33)

Exomes 𝑓: 0.0012 ( 1 hom. )

Consequence

NODAL
NM_018055.5 3_prime_UTR

Scores

Clinical Significance

Benign criteria provided, single submitter B:2

Conservation

PhyloP100: -1.65

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.9).

BP6

Variant 10-70432457-G-A is Benign according to our data. Variant chr10-70432457-G-A is described in ClinVar as [Benign]. Clinvar id is 300294.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0101 (1541/152286) while in subpopulation AFR AF= 0.0351 (1460/41550). AF 95% confidence interval is 0.0336. There are 23 homozygotes in gnomad4. There are 727 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd at 1534 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	#exon/exons	MANE
NODAL	NM_018055.5 linkuse as main transcript	c.*479C>T	3_prime_UTR_variant	3/3	ENST00000287139.8
NODAL	NM_001329906.2 linkuse as main transcript	c.*479C>T	3_prime_UTR_variant	3/3
NODAL	XM_024448028.2 linkuse as main transcript	c.*479C>T	3_prime_UTR_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NODAL	ENST00000287139.8 linkuse as main transcript	c.*479C>T		3_prime_UTR_variant	3/3	1	NM_018055.5	P1

Frequencies

GnomAD3 genomes

AF:

0.0101

AC:

1534

AN:

152168

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0351

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00347

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000103

Gnomad OTH

AF:

0.0100

GnomAD4 exome

AF:

0.00119

AC:

AN:

45282

Hom.:

Cov.:

AF XY:

0.00106

AC XY:

AN XY:

23536

show subpopulations

Gnomad4 AFR exome

AF:

0.0295

Gnomad4 AMR exome

AF:

0.00223

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000316

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00135

GnomAD4 genome

AF:

0.0101

AC:

1541

AN:

152286

Hom.:

Cov.:

AF XY:

0.00976

AC XY:

727

AN XY:

74460

show subpopulations

Gnomad4 AFR

AF:

0.0351

Gnomad4 AMR

AF:

0.00346

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000103

Gnomad4 OTH

AF:

0.00994

Alfa

AF:

0.00781

Hom.:

Bravo

AF:

0.0121

Asia WGS

AF:

0.00144

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Holoprosencephaly sequence

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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. -

Heterotaxy, visceral, 5, autosomal

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.90

Cadd

Benign

0.053

Dann

Benign

0.36

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over