chr10-70432214-C-G

Variant names:

• chr10-70432214-C-G
• rs2279254
• NM_018055.5:c.*722G>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.182
• Publications: 6 publications found

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

ACMG classification

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.: 34

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

African (AFR) AF: 0.500 AC: 1 AN: 2

American (AMR) AF: 0.445 AC: 81 AN: 182

Ashkenazi Jewish (ASJ) AF: 0.250 AC: 1 AN: 4

East Asian (EAS) AF: 0.571 AC: 8 AN: 14

South Asian (SAS) AF: 0.500 AC: 12 AN: 24

European-Finnish (FIN) AF: 0.500 AC: 2 AN: 4

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.518 AC: 380 AN: 734

Other (OTH) AF: 0.500 AC: 19 AN: 38

GnomAD4 genome AF: 0.439 AC: 66845 AN: 152196 Hom.: 15701 Cov.: 34 AF XY: 0.443 AC XY: 32972 AN XY: 74416

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

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

Pathogenic	VUS	Benign	Condition
-	-	1	Heterotaxy, visceral, 5, autosomal (1)
-	-	1	Holoprosencephaly sequence (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	5.8
DANN	Benign	0.53
PhyloP100		0.18

Splicing

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

Other links and lift over

dbSNP: rs2279254; hg19: chr10-72191970;