NM_001144967.3:c.2036A>G

Variant names:

• chr18-58366201-A-G
• rs879255599
• NM_001144967.3:c.2036A>G

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PP3_Moderate PP5

The NM_001144967.3(NEDD4L):​c.2036A>G​(p.Tyr679Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: NEDD4L NM_001144967.3 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:2
• Conservation: PhyloP100: 9.25
• Publications: 7 publications found

Genes affected

NEDD4L (HGNC:7728): (NEDD4 like E3 ubiquitin protein ligase) This gene encodes a member of the Nedd4 family of HECT domain E3 ubiquitin ligases. HECT domain E3 ubiquitin ligases transfer ubiquitin from E2 ubiquitin-conjugating enzymes to protein substrates, thus targeting specific proteins for lysosomal degradation. The encoded protein mediates the ubiquitination of multiple target substrates and plays a critical role in epithelial sodium transport by regulating the cell surface expression of the epithelial sodium channel, ENaC. Single nucleotide polymorphisms in this gene may be associated with essential hypertension. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Mar 2012]

NEDD4L Gene-Disease associations (from GenCC):

• periventricular nodular heterotopia 7

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics, G2P
• periventricular nodular heterotopia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.911
• PP5: Variant 18-58366201-A-G is Pathogenic according to our data. Variant chr18-58366201-A-G is described in ClinVar as Pathogenic. ClinVar VariationId is 225193.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001144967.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NEDD4L	NM_001144967.3	MANE Select	c.2036A>G	p.Tyr679Cys	missense	Exon 21 of 31	NP_001138439.1
	NEDD4L	NM_001437337.1		c.2873A>G	p.Tyr958Cys	missense	Exon 17 of 27	NP_001424266.1
	NEDD4L	NM_001144968.2		c.2012A>G	p.Tyr671Cys	missense	Exon 21 of 31	NP_001138440.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NEDD4L	ENST00000400345.8	TSL:1 MANE Select	c.2036A>G	p.Tyr679Cys	missense	Exon 21 of 31	ENSP00000383199.2
	NEDD4L	ENST00000357895.9	TSL:1	c.2012A>G	p.Tyr671Cys	missense	Exon 21 of 31	ENSP00000350569.4
	NEDD4L	ENST00000382850.8	TSL:1	c.1976A>G	p.Tyr659Cys	missense	Exon 20 of 30	ENSP00000372301.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: no assertion criteria provided

Submissions by phenotype

Periventricular nodular heterotopia with syndactyly, cleft palate and developmental delay Pathogenic:1

Apr 06, 2016

Chelly Lab, Institut de Génétique et de Biologie Moléculaire et Cellulaire, Strasbourg University - CNRS UMR 7104 - Inserm U 964

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

Periventricular nodular heterotopia 7 Pathogenic:1

Nov 16, 2016

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.25
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Benign	0.34	T
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.94
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D
M_CAP	Uncertain	0.18	D
MetaRNN	Pathogenic	0.91	D
MetaSVM	Uncertain	0.12	D
MutationAssessor	Pathogenic	3.5	H
PhyloP100		9.2
PrimateAI	Pathogenic	0.94	D
PROVEAN	Pathogenic	-8.4	D
REVEL	Pathogenic	0.68
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.78
MutPred		0.64		Gain of catalytic residue at P678 (P = 0.0576)
MVP		0.75
MPC		2.4
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.96
gMVP		0.69
Mutation Taster		=1/99	disease causing (ClinVar)

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: rs879255599; hg19: chr18-56033433;