10-70432196-A-G

Position:

• chr10-70432196-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

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
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 1.55

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 -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 id is 300288.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr10-70432196-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.702 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NODAL	NM_018055.5	c.*740T>C		3_prime_UTR_variant	3/3	ENST00000287139.8	NP_060525.3
NODAL	NM_001329906.2	c.*740T>C		3_prime_UTR_variant	3/3		NP_001316835.1
NODAL	XM_024448028.2	c.*740T>C		3_prime_UTR_variant	3/3		XP_024303796.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NODAL	ENST00000287139.8	c.*740T>C		3_prime_UTR_variant	3/3	1	NM_018055.5	ENSP00000287139.3

Frequencies

GnomAD3 genomes AF: 0.463 AC: 70400 AN: 151994 Hom.: 16960 Cov.: 34

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.: 99 AF XY: 0.489 AC XY: 215 AN XY: 440

Gnomad4 AFR exome AF: 0.500

Gnomad4 AMR exome AF: 0.468

Gnomad4 ASJ exome AF: 0.250

Gnomad4 EAS exome AF: 0.500

Gnomad4 SAS exome AF: 0.500

Gnomad4 NFE exome AF: 0.500

Gnomad4 OTH exome AF: 0.450

GnomAD4 genome AF: 0.463 AC: 70435 AN: 152112 Hom.: 16972 Cov.: 34 AF XY: 0.467 AC XY: 34732 AN XY: 74364

Gnomad4 AFR AF: 0.356

Gnomad4 AMR AF: 0.473

Gnomad4 ASJ AF: 0.413

Gnomad4 EAS AF: 0.721

Gnomad4 SAS AF: 0.496

Gnomad4 FIN AF: 0.515

Gnomad4 NFE AF: 0.497

Gnomad4 OTH AF: 0.481

Alfa AF: 0.490 Hom.: 31628

Bravo AF: 0.454

Asia WGS AF: 0.598 AC: 2078 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

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. -

Heterotaxy, visceral, 5, autosomal 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	-0.57
CADD	Benign	12
DANN	Benign	0.49

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs2279253; hg19: chr10-72191952;