chr10-70435683-T-C

Variant names:

• chr10-70435683-T-C
• rs1904589
• NM_018055.5:c.494A>G

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.494A>G​(p.His165Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.583 in 1,613,808 control chromosomes in the GnomAD database, including 278,726 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H165Y) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.57 (25425 hom., cov: 32)
  • Exomes 𝑓: 0.58 (253301 hom.)
• Consequence: NODAL NM_018055.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -0.0130
• Publications: 46 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

ENSG00000280401 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=7.5708806E-7).
• BP6: Variant 10-70435683-T-C is Benign according to our data. Variant chr10-70435683-T-C is described in ClinVar as Benign. ClinVar VariationId is 95882.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.932 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.494A>G	p.His165Arg	missense	Exon 2 of 3	NP_060525.3
	NODAL	NM_001329906.2		c.95A>G	p.His32Arg	missense	Exon 2 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.494A>G	p.His165Arg	missense	Exon 2 of 3	ENSP00000287139.3	Q96S42
	NODAL	ENST00000414871.1	TSL:1	c.329A>G	p.His110Arg	missense	Exon 2 of 3	ENSP00000394468.1	H7C0E4
	ENSG00000280401	ENST00000624563.1	TSL:6	n.855T>C		non_coding_transcript_exon	Exon 1 of 1

Frequencies

GnomAD3 genomes AF: 0.570 AC: 86568 AN: 151936 Hom.: 25388 Cov.: 32

Gnomad AFR AF: 0.510

Gnomad AMI AF: 0.522

Gnomad AMR AF: 0.626

Gnomad ASJ AF: 0.459

Gnomad EAS AF: 0.954

Gnomad SAS AF: 0.685

Gnomad FIN AF: 0.593

Gnomad MID AF: 0.633

Gnomad NFE AF: 0.558

Gnomad OTH AF: 0.573

GnomAD2 exomes AF: 0.618 AC: 155053 AN: 250940 AF XY: 0.616

Gnomad AFR exome AF: 0.500

Gnomad AMR exome AF: 0.677

Gnomad ASJ exome AF: 0.460

Gnomad EAS exome AF: 0.950

Gnomad FIN exome AF: 0.590

Gnomad NFE exome AF: 0.568

Gnomad OTH exome AF: 0.599

GnomAD4 exome AF: 0.584 AC: 853504 AN: 1461754 Hom.: 253301 Cov.: 82 AF XY: 0.586 AC XY: 425890 AN XY: 727172

African (AFR) AF: 0.508 AC: 17008 AN: 33480

American (AMR) AF: 0.670 AC: 29943 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.460 AC: 12022 AN: 26136

East Asian (EAS) AF: 0.950 AC: 37700 AN: 39698

South Asian (SAS) AF: 0.669 AC: 57703 AN: 86252

European-Finnish (FIN) AF: 0.590 AC: 31490 AN: 53354

Middle Eastern (MID) AF: 0.566 AC: 3262 AN: 5766

European-Non Finnish (NFE) AF: 0.566 AC: 628999 AN: 1111968

Other (OTH) AF: 0.586 AC: 35377 AN: 60388

GnomAD4 genome AF: 0.570 AC: 86643 AN: 152054 Hom.: 25425 Cov.: 32 AF XY: 0.576 AC XY: 42799 AN XY: 74328

African (AFR) AF: 0.510 AC: 21143 AN: 41472

American (AMR) AF: 0.627 AC: 9575 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.459 AC: 1590 AN: 3464

East Asian (EAS) AF: 0.954 AC: 4937 AN: 5174

South Asian (SAS) AF: 0.685 AC: 3304 AN: 4820

European-Finnish (FIN) AF: 0.593 AC: 6271 AN: 10578

Middle Eastern (MID) AF: 0.639 AC: 188 AN: 294

European-Non Finnish (NFE) AF: 0.558 AC: 37942 AN: 67950

Other (OTH) AF: 0.577 AC: 1218 AN: 2112

Alfa AF: 0.571 Hom.: 100892

Bravo AF: 0.569

TwinsUK AF: 0.549 AC: 2035

ALSPAC AF: 0.563 AC: 2171

ESP6500AA AF: 0.506 AC: 2230

ESP6500EA AF: 0.555 AC: 4775

ExAC AF: 0.616 AC: 74820

Asia WGS AF: 0.796 AC: 2770 AN: 3478

EpiCase AF: 0.559

EpiControl AF: 0.554

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	Heterotaxy, visceral, 5, autosomal (4)
-	-	3	not provided (3)
-	-	3	not specified (3)
-	-	1	Holoprosencephaly sequence (1)
-	-	1	NODAL-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.72	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	1.7
DANN	Benign	0.34
DEOGEN2	Benign	0.38	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.047	N
LIST_S2	Benign	0.086	T
MetaRNN	Benign	7.6e-7	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		-0.013
PrimateAI	Benign	0.21	T
PROVEAN	Benign	-0.39	N
REVEL	Benign	0.098
Sift	Benign	0.57	T
Sift4G	Benign	0.72	T
Polyphen		0.0	B
Vest4		0.0050
MPC		0.38
ClinPred		0.0041	T
GERP RS		-2.8
Varity_R		0.035
gMVP		0.18
Mutation Taster		=96/4	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1904589; hg19: chr10-72195439; COSMIC: COSV54660789;