chr10-70435515-C-T

Position:

• chr10-70435515-C-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_018055.5(NODAL):​c.662G>A​(p.Arg221Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000233 in 1,614,088 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00014 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00024 (0 hom.)
• Consequence: NODAL NM_018055.5 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.68

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]

ENSG00000280401 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.03165424).
• BP6: Variant 10-70435515-C-T is Benign according to our data. Variant chr10-70435515-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 215899.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd4 at 21 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NODAL	NM_018055.5	c.662G>A	p.Arg221Gln	missense_variant	2/3	ENST00000287139.8	NP_060525.3
NODAL	NM_001329906.2	c.263G>A	p.Arg88Gln	missense_variant	2/3		NP_001316835.1
NODAL	XM_024448028.2	c.263G>A	p.Arg88Gln	missense_variant	2/3		XP_024303796.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NODAL	ENST00000287139.8	c.662G>A	p.Arg221Gln	missense_variant	2/3	1	NM_018055.5	ENSP00000287139.3
NODAL	ENST00000414871.1	c.497G>A	p.Arg166Gln	missense_variant	2/3	1		ENSP00000394468.1
ENSG00000280401	ENST00000624563.1	n.687C>T		non_coding_transcript_exon_variant	1/1	6

Frequencies

GnomAD3 genomes AF: 0.000138 AC: 21 AN: 152178 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000771

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.000279 AC: 70 AN: 251286 Hom.: 0 AF XY: 0.000272 AC XY: 37 AN XY: 135844

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.000347

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00147

Gnomad SAS exome AF: 0.000261

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000185

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000243 AC: 355 AN: 1461792 Hom.: 0 Cov.: 29 AF XY: 0.000246 AC XY: 179 AN XY: 727212

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.000335

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000781

Gnomad4 SAS exome AF: 0.000290

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000234

Gnomad4 OTH exome AF: 0.000364

GnomAD4 genome AF: 0.000138 AC: 21 AN: 152296 Hom.: 0 Cov.: 32 AF XY: 0.000188 AC XY: 14 AN XY: 74468

Gnomad4 AFR AF: 0.0000722

Gnomad4 AMR AF: 0.0000653

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000773

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000162

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.000164 Hom.: 0

Bravo AF: 0.000144

ExAC AF: 0.000305 AC: 37

EpiCase AF: 0.000218

EpiControl AF: 0.000356

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Heterotaxy, visceral, 5, autosomal Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 12, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Uncertain	-0.030
CADD	Uncertain	24
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.44	T;T
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.84	T;T
M_CAP	Benign	0.061	D
MetaRNN	Benign	0.032	T;T
MetaSVM	Uncertain	0.19	D
MutationAssessor	Uncertain	2.4	M;.
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-0.36	N;N
REVEL	Uncertain	0.44
Sift	Benign	0.36	T;T
Sift4G	Benign	0.29	T;T
Polyphen		1.0	D;.
Vest4		0.47
MVP		0.78
MPC		1.1
ClinPred		0.10	T
GERP RS		5.9
Varity_R		0.13
gMVP		0.69

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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

Other links and lift over

dbSNP: rs138681813; hg19: chr10-72195271;