ENST00000431212.6:c.-79C>T

Variant names:

• chr18-58252042-C-T
• rs185602532
• ENST00000431212.6:c.-79C>T

GermlineCancer (beta)

Variant summary

Our verdict is Uncertain significance.

+1 Uncertain · Cold

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 1 classification points (ACGS-UK Somatic Oncogenicity v2025). O3_Supporting

The ENST00000431212.6(NEDD4L):c.-79C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. Note: ENST00000431212.6 is not a MANE Select or MANE Plus Clinical transcript for NEDD4L; the reported annotation may differ from that of the MANE-designated reference transcript for this gene. The gene NEDD4L is a tumor suppressor gene (CancerMine: 18 TSG, 1 oncogene citations). The gene NEDD4L is a known oncogene (CancerMine: 18 TSG, 1 oncogene citations). The variant allele was found at a cumulative frequency of 0.0000339 (AC=54) in the gnomAD database across 1,591,712 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.0000887. In-silico predictor (BayesDel (noAF)) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign/Likely Benign (★★). The variant has been observed in cBioPortal in 2 samples across 2 studies and 2 cancer types; somatic enrichment level: SUPPORTING_LOW (Observed in a small number of cBioPortal cases.).

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000033 (0 hom.)
• Consequence: NEDD4L ENST00000431212.6 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.259
• Publications: 2 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: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen, PanelApp Australia
• periventricular nodular heterotopia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

Classification according to ACGS-UK Somatic Oncogenicity v2025

Classification was made for transcript:

Our verdict: Uncertain_significance. The variant received 1 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	O3Absent or very rare in population		Very rare in gnomAD (popmax AF <0.01%) — O3 supporting; GnomAD effective popmax AF = 0.000089 — very rare (O3 supporting [+1])

Variant Effect in Transcripts

Automated classification analysis was done for transcript: ENST00000431212.6. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NEDD4L	NM_001144967.3	MANE Select	c.285C>T	p.Asp95Asp	synonymous	Exon 5 of 31	NP_001138439.1	Q96PU5-1
	NEDD4L	NM_001144964.1		c.-79C>T		5_prime_UTR_premature_start_codon_gain	Exon 5 of 31	NP_001138436.1	Q96PU5-4
	NEDD4L	NM_001144965.2		c.-79C>T		5_prime_UTR_premature_start_codon_gain	Exon 5 of 31	NP_001138437.1	Q96PU5-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NEDD4L	ENST00000431212.6	TSL:1	c.-79C>T		5_prime_UTR_premature_start_codon_gain	Exon 4 of 30	ENSP00000389406.1	Q96PU5-4
	NEDD4L	ENST00000456986.5	TSL:1	c.-79C>T		5_prime_UTR_premature_start_codon_gain	Exon 5 of 31	ENSP00000411947.1	Q96PU5-4
	NEDD4L	ENST00000435432.6	TSL:1	c.-79C>T		5_prime_UTR_premature_start_codon_gain	Exon 6 of 31	ENSP00000393395.1	Q96PU5-9

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 6 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.0000460	AC:7	Hom:0	AN:152080	Cov:32
GnomAD2 exomes	AF: 0.0000562	AC:14	Hom:	AN:248994	Cov:
GnomAD4 exome	AF: 0.0000326	AC:47	Hom:0	AN:1439632	Cov:26
GnomAD4 genome	AF: 0.0000460	AC:7	Hom:0	AN:152080	Cov:32
TOPMed (Bravo)	AF: 0.0000567	AC:	Hom:	AN:	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.0000550	AC:3	Hom:0	AN:54580	Cov:
Local & regional cohorts 2 sources Population-specific and national genomic databases
GenomeAsia100K	AF: 0.000289	AC:1	Hom:	AN:3476	Cov:
Korea4K (4,157 Koreans)	AF: 0.000138	AC:1	Hom:	AN:7232	Cov:

Showing 8 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
BipEx(Bipolar disorder (including schizoaffective))	0.0000352	1	28420	0.0000347	1	28844
Epi25(Epilepsy)	0.0000477	2	41948	0.0000299	2	66876
SCHEMA(Schizophrenia)	0.0000708	8	113064	0.0000997	19	190536

Showing 3 cohortsAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	Periventricular nodular heterotopia 7 (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Benign	0.64
BayesDel_noAF	Benign	-0.43
CADD	Benign	9.5
DANN	Benign	0.51
GPN-Star LLR	N/A	-1.7
GPN-Star score	N/A	1.5
Mutation Taster	N/A	96/4	polymorphism
PhyloP100	Benign	0.26
RBP_binding_hub_radar	N/A	0.0
RBP_regulation_power_radar	N/A	1.7

Showing 10 of 10 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.010
SpliceAI score (max)	Benign	0.010	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs185602532;

hg19: chr18-55919274;

COSMIC: COSV56846423;

COSMIC: COSV56846423;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar