rs10999338

Variant names:

• chr10-70441463-G-A
• rs10999338
• NM_018055.5:c.193+12C>T

Your query was ambiguous. Multiple possible variants found:

• chr10-70441463-G-A
• chr10-70441463-G-C
• chr10-70441463-G-T

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.193+12C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.432 in 1,565,208 control chromosomes in the GnomAD database, including 152,519 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.36 (11442 hom., cov: 34)
  • Exomes 𝑓: 0.44 (141077 hom.)
• Consequence: NODAL NM_018055.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -0.129
• Publications: 10 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=-0.77).
• BP6: Variant 10-70441463-G-A is Benign according to our data. Variant chr10-70441463-G-A is described in ClinVar as Benign. ClinVar VariationId is 95881.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.603 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.193+12C>T		intron	N/A	NP_060525.3
	NODAL	NM_001329906.2		c.-206-5480C>T		intron	N/A	NP_001316835.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NODAL	ENST00000287139.8	TSL:1 MANE Select	c.193+12C>T		intron	N/A	ENSP00000287139.3	Q96S42
	NODAL	ENST00000414871.1	TSL:1	c.29-5480C>T		intron	N/A	ENSP00000394468.1	H7C0E4

Frequencies

GnomAD3 genomes AF: 0.357 AC: 54291 AN: 152076 Hom.: 11438 Cov.: 34

Gnomad AFR AF: 0.140

Gnomad AMI AF: 0.446

Gnomad AMR AF: 0.412

Gnomad ASJ AF: 0.307

Gnomad EAS AF: 0.622

Gnomad SAS AF: 0.276

Gnomad FIN AF: 0.420

Gnomad MID AF: 0.478

Gnomad NFE AF: 0.453

Gnomad OTH AF: 0.376

GnomAD2 exomes AF: 0.399 AC: 67551 AN: 169238 AF XY: 0.396

Gnomad AFR exome AF: 0.131

Gnomad AMR exome AF: 0.371

Gnomad ASJ exome AF: 0.312

Gnomad EAS exome AF: 0.636

Gnomad FIN exome AF: 0.426

Gnomad NFE exome AF: 0.455

Gnomad OTH exome AF: 0.409

GnomAD4 exome AF: 0.440 AC: 621837 AN: 1413016 Hom.: 141077 Cov.: 42 AF XY: 0.436 AC XY: 304700 AN XY: 699372

African (AFR) AF: 0.128 AC: 4139 AN: 32290

American (AMR) AF: 0.374 AC: 14206 AN: 37988

Ashkenazi Jewish (ASJ) AF: 0.309 AC: 7858 AN: 25408

East Asian (EAS) AF: 0.558 AC: 20460 AN: 36656

South Asian (SAS) AF: 0.272 AC: 21920 AN: 80734

European-Finnish (FIN) AF: 0.432 AC: 19789 AN: 45804

Middle Eastern (MID) AF: 0.380 AC: 2042 AN: 5374

European-Non Finnish (NFE) AF: 0.465 AC: 506976 AN: 1090078

Other (OTH) AF: 0.417 AC: 24447 AN: 58684

GnomAD4 genome AF: 0.357 AC: 54291 AN: 152192 Hom.: 11442 Cov.: 34 AF XY: 0.357 AC XY: 26548 AN XY: 74400

African (AFR) AF: 0.140 AC: 5802 AN: 41562

American (AMR) AF: 0.412 AC: 6310 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.307 AC: 1063 AN: 3468

East Asian (EAS) AF: 0.621 AC: 3198 AN: 5150

South Asian (SAS) AF: 0.277 AC: 1335 AN: 4826

European-Finnish (FIN) AF: 0.420 AC: 4448 AN: 10598

Middle Eastern (MID) AF: 0.490 AC: 144 AN: 294

European-Non Finnish (NFE) AF: 0.453 AC: 30787 AN: 67972

Other (OTH) AF: 0.378 AC: 798 AN: 2112

Alfa AF: 0.381 Hom.: 2204

Bravo AF: 0.348

Asia WGS AF: 0.389 AC: 1353 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	3	Heterotaxy, visceral, 5, autosomal (3)
-	-	2	not provided (2)
-	-	1	Holoprosencephaly sequence (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	3.1
DANN	Benign	0.95
PhyloP100		-0.13
PromoterAI		0.055	Neutral
Mutation Taster		=100/0	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: rs10999338; hg19: chr10-72201219; COSMIC: COSV54660797; COSMIC: COSV54660797;