chr18-58044673-C-T

Position:

• chr18-58044673-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_001144967.3(NEDD4L):​c.13C>T​(p.Leu5Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000593 in 1,604,176 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. L5L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00049 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00060 (0 hom.)
• Consequence: NEDD4L NM_001144967.3 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.103

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]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.040255338).
• BP6: Variant 18-58044673-C-T is Benign according to our data. Variant chr18-58044673-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 695592.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 74 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NEDD4L	NM_001144967.3	c.13C>T	p.Leu5Phe	missense_variant	1/31	ENST00000400345.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NEDD4L	ENST00000400345.8	c.13C>T	p.Leu5Phe	missense_variant	1/31	1	NM_001144967.3	P3

Frequencies

GnomAD3 genomes AF: 0.000487 AC: 74 AN: 152036 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000883

Gnomad OTH AF: 0.000955

GnomAD3 exomes AF: 0.000549 AC: 128 AN: 233240 Hom.: 0 AF XY: 0.000575 AC XY: 74 AN XY: 128664

Gnomad AFR exome AF: 0.000224

Gnomad AMR exome AF: 0.000183

Gnomad ASJ exome AF: 0.000417

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000937

Gnomad NFE exome AF: 0.00107

Gnomad OTH exome AF: 0.000178

GnomAD4 exome AF: 0.000605 AC: 878 AN: 1452030 Hom.: 0 Cov.: 31 AF XY: 0.000608 AC XY: 439 AN XY: 722328

Gnomad4 AFR exome AF: 0.000185

Gnomad4 AMR exome AF: 0.000228

Gnomad4 ASJ exome AF: 0.000348

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000117

Gnomad4 FIN exome AF: 0.000229

Gnomad4 NFE exome AF: 0.000729

Gnomad4 OTH exome AF: 0.000534

GnomAD4 genome AF: 0.000486 AC: 74 AN: 152146 Hom.: 0 Cov.: 32 AF XY: 0.000390 AC XY: 29 AN XY: 74382

Gnomad4 AFR AF: 0.0000722

Gnomad4 AMR AF: 0.000261

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000283

Gnomad4 NFE AF: 0.000883

Gnomad4 OTH AF: 0.000945

Alfa AF: 0.000959 Hom.: 0

Bravo AF: 0.000514

ESP6500AA AF: 0.000283 AC: 1

ESP6500EA AF: 0.000249 AC: 2

ExAC AF: 0.000749 AC: 90

ClinVar

Significance: Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2023	NEDD4L: BS1 -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

NEDD4L-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 27, 2024

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.21	.;T;.;.;.;.
Eigen	Benign	-0.065
Eigen_PC	Benign	-0.049
FATHMM_MKL	Benign	0.33	N
LIST_S2	Benign	0.57	T;T;T;.;T;T
M_CAP	Pathogenic	0.41	D
MetaRNN	Benign	0.040	T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.81	L;L;.;.;L;L
MutationTaster	Benign	1.0	D;N;N;N;N;N
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-0.26	N;N;.;.;N;N
REVEL	Benign	0.026
Sift	Benign	0.14	T;T;.;.;T;T
Sift4G	Benign	0.35	T;T;T;.;T;T
Polyphen		0.89	P;P;.;.;P;.
Vest4		0.12
MVP		0.53
MPC		0.45
ClinPred		0.091	T
GERP RS		3.3
Varity_R		0.14
gMVP		0.12

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

Publications

LitVar

Other links and lift over

dbSNP: rs201307997; hg19: chr18-55711905;