ENST00000354646.7:c.4775T>C

Variant names:

• chrX-54232874-A-G
• rs782290033
• ENST00000354646.7:c.4775T>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The ENST00000354646.7(WNK3):​c.4775T>C​(p.Phe1592Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000018 (0 hom., 1 hem., cov: 22)
  • Failed GnomAD Quality Control
• Consequence: WNK3 ENST00000354646.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.33
• Publications: 0 publications found

Genes affected

WNK3 (HGNC:14543): (WNK lysine deficient protein kinase 3) This gene encodes a protein belonging to the 'with no lysine' family of serine-threonine protein kinases. These family members lack the catalytic lysine in subdomain II, and instead have a conserved lysine in subdomain I. This family member functions as a positive regulator of the transcellular Ca2+ transport pathway, and it plays a role in the increase of cell survival in a caspase-3-dependent pathway. Alternative splicing results in multiple transcript variants. [provided by RefSeq, May 2010]

WNK3 Gene-Disease associations (from GenCC):

• Prieto syndrome

  Inheritance: XL Classification: MODERATE Submitted by: G2P

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.16845766).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WNK3	NM_020922.5	c.4775T>C	p.Phe1592Ser	missense_variant	Exon 21 of 24		NP_065973.2
WNK3	NM_001002838.4	c.4634T>C	p.Phe1545Ser	missense_variant	Exon 21 of 23		NP_001002838.1
WNK3	NM_001395166.1	c.4634T>C	p.Phe1545Ser	missense_variant	Exon 21 of 23		NP_001382095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WNK3	ENST00000354646.7	c.4775T>C	p.Phe1592Ser	missense_variant	Exon 21 of 24	1		ENSP00000346667.2
WNK3	ENST00000375169.7	c.4634T>C	p.Phe1545Ser	missense_variant	Exon 21 of 23	5		ENSP00000364312.3

Frequencies

GnomAD3 genomes AF: 0.0000180 AC: 2 AN: 111350 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000376

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000545 AC: 1 AN: 183518 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000122

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 30

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000180 AC: 2 AN: 111350 Hom.: 0 Cov.: 22 AF XY: 0.0000298 AC XY: 1 AN XY: 33528

African (AFR) AF: 0.00 AC: 0 AN: 30654

American (AMR) AF: 0.00 AC: 0 AN: 10341

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2650

East Asian (EAS) AF: 0.00 AC: 0 AN: 3562

South Asian (SAS) AF: 0.00 AC: 0 AN: 2630

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5930

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 240

European-Non Finnish (NFE) AF: 0.0000376 AC: 2 AN: 53165

Other (OTH) AF: 0.00 AC: 0 AN: 1494

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 19, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.4775T>C (p.F1592S) alteration is located in exon 21 (coding exon 20) of the WNK3 gene. This alteration results from a T to C substitution at nucleotide position 4775, causing the phenylalanine (F) at amino acid position 1592 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Benign	-0.096	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Benign	0.051	.;T;T;.
FATHMM_MKL	Benign	0.73	D
LIST_S2	Benign	0.79	T;T;.;T
M_CAP	Uncertain	0.17	D
MetaRNN	Benign	0.17	T;T;T;T
MetaSVM	Benign	-0.78	T
MutationAssessor	Benign	0.47	.;N;N;.
PhyloP100		4.3
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.21	N;N;N;.
REVEL	Benign	0.20
Sift	Benign	0.36	T;T;T;.
Sift4G	Benign	0.74	T;T;T;T
Polyphen		0.66	P;P;P;.
Vest4		0.35
MutPred		0.35		.;Gain of phosphorylation at F1592 (P = 8e-04);Gain of phosphorylation at F1592 (P = 8e-04);Gain of phosphorylation at F1592 (P = 8e-04);
MVP		0.60
MPC		0.38
ClinPred		0.38	T
GERP RS		5.7
Varity_R		0.25
gMVP		0.11
Mutation Taster		=97/3	polymorphism

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: rs782290033; hg19: chrX-54259307;