ENST00000431212.6:c.-79C>T

Variant names:

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

GermlineCancer (beta)

Variant summary

Our verdict is Benign.

-9 Benign

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received -9 classification points (ACMG Germline Pathogenicity v2019). PM2_SupportingBS2BP4_ModerateBP6_Strong

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 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 (★★).

• 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 ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Benign. The variant received -9 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PM2Absent/extremely low in population databases		Rare in gnomAD for AD/XL gene (popmax AF below threshold) — PM2 Supporting; GnomAD popmax AF = 0.0000887 — borderline rare for AD/XL gene (threshold 0.0001) — PM2 supporting.
	BP4Computational evidence suggests no impact		Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Moderate).
	BP6Reputable source reports benign		ClinVar 2-star benign — strong (BP6); ClinVar germline classification: Benign/Likely Benign, 2 star(s).
	BS2Observed in healthy adult		Pure AD gene with cumulative gnomAD AC ≥5 — observed in healthy adults (BS2); GnomAD homozygous count = 0.; Cumulative gnomAD AC = 54 (pure AD gene, not AR).

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	Prot: NP_001138439.1 UniProt:
	NEDD4L NM_001144964.1		c.-79C>T	5_prime_UTR_premature_start_codon_gain	Exon 5 of 31	Prot: NP_001138436.1 UniProt:
	NEDD4L NM_001144965.2		c.-79C>T	5_prime_UTR_premature_start_codon_gain	Exon 5 of 31	Prot: NP_001138437.1 UniProt:

NEDD4L NM_001144967.3

MANE Select

HGVSc / HGVSpc.285C>Tp.Asp95Asp

Exon rankExon 5 of 31

synonymous

Prot: NP_001138439.1UniProt: Q96PU5-1

NEDD4L NM_001144964.1

HGVSc / HGVSpc.-79C>T

Exon rankExon 5 of 31

5_prime_UTR_premature_start_codon_gain

Prot: NP_001138436.1UniProt: Q96PU5-4

NEDD4L NM_001144965.2

HGVSc / HGVSpc.-79C>T

Exon rankExon 5 of 31

5_prime_UTR_premature_start_codon_gain

Prot: NP_001138437.1UniProt: 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	Prot: ENSP00000389406.1 UniProt:
	NEDD4L ENST00000456986.5	TSL:1	c.-79C>T	5_prime_UTR_premature_start_codon_gain	Exon 5 of 31	Prot: ENSP00000411947.1 UniProt:
	NEDD4L ENST00000435432.6	TSL:1	c.-79C>T	5_prime_UTR_premature_start_codon_gain	Exon 6 of 31	Prot: ENSP00000393395.1 UniProt:

NEDD4L ENST00000431212.6

TSL:1

HGVSc / HGVSpc.-79C>T

Exon rankExon 4 of 30

5_prime_UTR_premature_start_codon_gain

Prot: ENSP00000389406.1UniProt: Q96PU5-4

NEDD4L ENST00000456986.5

TSL:1

HGVSc / HGVSpc.-79C>T

Exon rankExon 5 of 31

5_prime_UTR_premature_start_codon_gain

Prot: ENSP00000411947.1UniProt: Q96PU5-4

NEDD4L ENST00000435432.6

TSL:1

HGVSc / HGVSpc.-79C>T

Exon rankExon 6 of 31

5_prime_UTR_premature_start_codon_gain

Prot: ENSP00000393395.1UniProt: 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.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

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