chr18-58044662-T-C

Position:

• chr18-58044662-T-C

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_001144967.3(NEDD4L):​c.2T>C​(p.Met1?) variant causes a start lost change involving the alteration of a non-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 Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: NEDD4L NM_001144967.3 start_lost
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.97

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 Pathogenic. Variant got 10 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NEDD4L	NM_001144967.3	c.2T>C	p.Met1?	start_lost	1/31	ENST00000400345.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NEDD4L	ENST00000400345.8	c.2T>C	p.Met1?	start_lost	1/31	1	NM_001144967.3	P3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Aug 29, 2023

This variant is not present in population databases (gnomAD no frequency). This sequence change affects the initiator methionine of the NEDD4L mRNA. The next in-frame methionine is located at codon 122. This variant has not been reported in the literature in individuals affected with NEDD4L-related conditions. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.040
CADD	Benign	23
DANN	Benign	0.94
Eigen	Benign	-0.40
Eigen_PC	Benign	-0.34
FATHMM_MKL	Benign	0.35	N
LIST_S2	Uncertain	0.90	D;D;D;.;D;D
M_CAP	Pathogenic	0.89	D
MetaRNN	Pathogenic	0.85	D;D;D;D;D;D
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	D;D;D;D;D;D
PROVEAN	Benign	-1.5	N;N;.;.;N;N
REVEL	Benign	0.18
Sift	Pathogenic	0.0	D;D;.;.;D;D
Sift4G	Pathogenic	0.0	D;D;.;.;D;D
Polyphen		0.020	B;B;.;.;B;.
Vest4		0.77
MutPred		0.56		Gain of catalytic residue at M1 (P = 0.0101);Gain of catalytic residue at M1 (P = 0.0101);Gain of catalytic residue at M1 (P = 0.0101);Gain of catalytic residue at M1 (P = 0.0101);Gain of catalytic residue at M1 (P = 0.0101);Gain of catalytic residue at M1 (P = 0.0101);
MVP		0.79
ClinPred		0.82	D
GERP RS		2.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.92
gMVP		0.50

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr18-55711894;