Genetic Variant ENST00000431212.6:c.-79C>T (chr18-58252042-C-T) – ACMG Classification: Benign (-9 pts)

Variant summary

Our verdict is 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 0.0000916. 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: 0.000031 ( 0 hom. )

Consequence

NEDD4L
ENST00000431212.6 5_prime_UTR_premature_start_codon_gain

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.259

Publications

2 publications found

Variant links:

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

NEDD4L links:

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript ENST00000431212.6, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript

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

PM2

Rare in gnomAD for AD/XL gene (popmax AF below threshold) — PM2 Supporting; GnomAD popmax AF = 0.0000916 — borderline rare for AD/XL gene (threshold 0.0001) — PM2 supporting.

BP4

Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Moderate).

BP6

ClinVar 2-star benign — strong (BP6); ClinVar germline classification: Benign/Likely Benign, 2 star(s).

BS2

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

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

Gene	Transcript	Tags	HGVSc	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

GnomAD3 genomes

AF:

0.0000458

AC:

AN:

152080

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000458

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000137

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000198

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000305

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000610

AC:

AN:

248994

AF XY:

0.0000610

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000229

Gnomad ASJ exome

AF:

0.000107

Gnomad EAS exome

AF:

0.0000610

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000305

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000305

AC:

AN:

1439632

Hom.:

Cov.:

AF XY:

0.0000305

AC XY:

AN XY:

717838

show subpopulations

African (AFR)

AF:

0.0000305

AC:

AN:

33026

American (AMR)

AF:

0.000183

AC:

AN:

44682

Ashkenazi Jewish (ASJ)

AF:

0.0000763

AC:

AN:

25998

East Asian (EAS)

AF:

0.0000458

AC:

AN:

39536

South Asian (SAS)

AF:

0.00

AC:

AN:

85806

European-Finnish (FIN)

AF:

0.0000153

AC:

AN:

53322

Middle Eastern (MID)

AF:

0.000168

AC:

AN:

5734

European-Non Finnish (NFE)

AF:

0.0000305

AC:

AN:

1091908

Other (OTH)

AF:

0.0000763

AC:

AN:

59620

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.451

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000458

AC:

AN:

152080

Hom.:

Cov.:

AF XY:

0.0000458

AC XY:

AN XY:

74290

show subpopulations

African (AFR)

AF:

0.0000458

AC:

AN:

41396

American (AMR)

AF:

0.000137

AC:

AN:

15268

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.000198

AC:

AN:

5206

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10586

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000305

AC:

AN:

68010

Other (OTH)

AF:

0.00

AC:

AN:

2082

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000610

Hom.:

Bravo

AF:

0.0000610

Asia WGS

AF:

0.000290

AC:

AN:

3476

EpiCase

AF:

0.0000610

EpiControl

AF:

0.00

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Periventricular nodular heterotopia 7 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.43

CADD

Benign

9.5

(source)

DANN

Benign

0.51

PhyloP100

0.26

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=96/4

polymorphism

(source)

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

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

Classification according to ACMG Germline Pathogenicity v2019

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over