18-58044386-T-G

Variant names:

• chr18-58044386-T-G
• rs4496245
• NM_001144967.3:c.-275T>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001144967.3(NEDD4L):​c.-275T>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.921 in 210,524 control chromosomes in the GnomAD database, including 89,557 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.93 (65362 hom., cov: 32)
  • Exomes 𝑓: 0.90 (24195 hom.)
• Consequence: NEDD4L NM_001144967.3 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.446
• Publications: 4 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: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics, ClinGen
• periventricular nodular heterotopia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 18-58044386-T-G is Benign according to our data. Variant chr18-58044386-T-G is described in ClinVar as Benign. ClinVar VariationId is 1251004.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.976 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001144967.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NEDD4L	NM_001144967.3	MANE Select	c.-275T>G		5_prime_UTR	Exon 1 of 31	NP_001138439.1	Q96PU5-1
	NEDD4L	NM_015277.6		c.-275T>G		5_prime_UTR	Exon 1 of 30	NP_056092.2
	NEDD4L	NM_001243960.2		c.-275T>G		5_prime_UTR	Exon 1 of 29	NP_001230889.1	Q96PU5-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NEDD4L	ENST00000400345.8	TSL:1 MANE Select	c.-275T>G		5_prime_UTR	Exon 1 of 31	ENSP00000383199.2	Q96PU5-1
	NEDD4L	ENST00000356462.10	TSL:1	c.-275T>G		5_prime_UTR	Exon 1 of 29	ENSP00000348847.5	Q96PU5-2
	NEDD4L	ENST00000936802.1		c.-275T>G		5_prime_UTR	Exon 1 of 29	ENSP00000606861.1

Frequencies

GnomAD3 genomes AF: 0.931 AC: 139955 AN: 150330 Hom.: 65302 Cov.: 32

Gnomad AFR AF: 0.982

Gnomad AMI AF: 0.906

Gnomad AMR AF: 0.934

Gnomad ASJ AF: 0.905

Gnomad EAS AF: 0.999

Gnomad SAS AF: 0.981

Gnomad FIN AF: 0.931

Gnomad MID AF: 0.882

Gnomad NFE AF: 0.893

Gnomad OTH AF: 0.926

GnomAD4 exome AF: 0.896 AC: 53853 AN: 60086 Hom.: 24195 Cov.: 3 AF XY: 0.893 AC XY: 28044 AN XY: 31400

African (AFR) AF: 0.977 AC: 1707 AN: 1748

American (AMR) AF: 0.936 AC: 1520 AN: 1624

Ashkenazi Jewish (ASJ) AF: 0.886 AC: 1808 AN: 2040

East Asian (EAS) AF: 1.00 AC: 3900 AN: 3900

South Asian (SAS) AF: 0.970 AC: 518 AN: 534

European-Finnish (FIN) AF: 0.921 AC: 5044 AN: 5474

Middle Eastern (MID) AF: 0.917 AC: 365 AN: 398

European-Non Finnish (NFE) AF: 0.877 AC: 35498 AN: 40496

Other (OTH) AF: 0.902 AC: 3493 AN: 3872

GnomAD4 genome AF: 0.931 AC: 140070 AN: 150438 Hom.: 65362 Cov.: 32 AF XY: 0.936 AC XY: 68756 AN XY: 73496

African (AFR) AF: 0.982 AC: 40576 AN: 41336

American (AMR) AF: 0.935 AC: 14145 AN: 15136

Ashkenazi Jewish (ASJ) AF: 0.905 AC: 3120 AN: 3448

East Asian (EAS) AF: 0.999 AC: 5062 AN: 5068

South Asian (SAS) AF: 0.981 AC: 4738 AN: 4832

European-Finnish (FIN) AF: 0.931 AC: 9277 AN: 9960

Middle Eastern (MID) AF: 0.887 AC: 259 AN: 292

European-Non Finnish (NFE) AF: 0.893 AC: 60132 AN: 67368

Other (OTH) AF: 0.927 AC: 1938 AN: 2090

Alfa AF: 0.891 Hom.: 2878

Bravo AF: 0.934

Asia WGS AF: 0.978 AC: 2996 AN: 3064

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	7.3
DANN	Benign	0.53
PhyloP100		-0.45
PromoterAI		0.025	Neutral
Mutation Taster		=300/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs4496245; hg19: chr18-55711618;