18-58329053-C-G

Variant names:

• chr18-58329053-C-G
• NM_001144967.3:c.739C>G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001144967.3(NEDD4L):​c.739C>G​(p.Arg247Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,674 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: NEDD4L NM_001144967.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.105

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NEDD4L	NM_001144967.3	c.739C>G	p.Arg247Gly	missense_variant	Exon 10 of 31	ENST00000400345.8	NP_001138439.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NEDD4L	ENST00000400345.8	c.739C>G	p.Arg247Gly	missense_variant	Exon 10 of 31	1	NM_001144967.3	ENSP00000383199.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461674 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727114

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.71
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.050
CADD	Benign	20
DANN	Benign	0.96
DEOGEN2	Uncertain	0.65	.;D;.;.;.;.;.;.;.;.;T;.;T
Eigen	Benign	-0.69
Eigen_PC	Benign	-0.77
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Benign	0.85	D;D;D;D;T;.;D;D;T;.;D;D;D
M_CAP	Benign	0.084	D
MetaRNN	Uncertain	0.50	D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.90	T
MutationAssessor	Uncertain	2.0	M;M;M;M;.;.;.;.;.;.;.;.;.
PrimateAI	Uncertain	0.77	T
PROVEAN	Uncertain	-2.5	D;D;D;D;D;D;D;.;D;D;.;.;.
REVEL	Benign	0.22
Sift	Uncertain	0.027	D;D;D;T;D;D;D;.;D;D;.;.;.
Sift4G	Benign	0.067	T;T;T;T;T;T;T;T;T;T;D;.;T
Polyphen		1.0	D;B;B;D;.;.;B;B;.;.;.;.;.
Vest4		0.87
MVP		0.68
MPC		0.91
ClinPred		0.95	D
GERP RS		-3.3
Varity_R		0.26
gMVP		0.67

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: chr18-55996285;