16-50608322-C-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_033119.5(NKD1):c.221C>A(p.Thr74Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,118 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T74A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: NKD1 NM_033119.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.674

Genes affected

NKD1 (HGNC:17045): (NKD inhibitor of WNT signaling pathway 1) In the mouse, Nkd is a Dishevelled (see DVL1; MIM 601365)-binding protein that functions as a negative regulator of the Wnt (see WNT1; MIM 164820)-beta-catenin (see MIM 116806)-Tcf (see MIM 602272) signaling pathway.[supplied by OMIM, Jun 2003]

(HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.060236096).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NKD1	NM_033119.5	c.221C>A	p.Thr74Lys	missense_variant	4/10	ENST00000268459.6
LOC124903773	XR_007065197.1	n.189G>T		non_coding_transcript_exon_variant	2/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NKD1	ENST00000268459.6	c.221C>A	p.Thr74Lys	missense_variant	4/10	1	NM_033119.5	P1
	ENST00000379963.1	n.223G>T		non_coding_transcript_exon_variant	2/2	2
NKD1	ENST00000564336.1	n.379C>A		non_coding_transcript_exon_variant	4/5	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000119 AC: 3 AN: 251196 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135778

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000163

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461118 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726900

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000126

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

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

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 09, 2023

The c.221C>A (p.T74K) alteration is located in exon 4 (coding exon 4) of the NKD1 gene. This alteration results from a C to A substitution at nucleotide position 221, causing the threonine (T) at amino acid position 74 to be replaced by a lysine (K). 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	0.14
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.46
Cadd	Benign	9.6
Dann	Benign	0.68
DEOGEN2	Benign	0.27	T
Eigen	Benign	-0.77
Eigen_PC	Benign	-0.75
FATHMM_MKL	Benign	0.25	N
LIST_S2	Benign	0.52	T
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.060	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.90	L
MutationTaster	Benign	1.0	N
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	0.060	N
REVEL	Benign	0.044
Sift	Benign	0.92	T
Sift4G	Benign	0.53	T
Polyphen		0.33	B
Vest4		0.31
MutPred		0.29		Gain of ubiquitination at T74 (P = 9e-04);
MVP		0.15
MPC		0.36
ClinPred		0.11	T
GERP RS		3.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.074
gMVP		0.54

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: rs756691004; hg19: chr16-50642233;