chr19-16744671-G-T

Position:

• chr19-16744671-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001290355.3(NWD1):​c.-386G>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: NWD1 NM_001290355.3 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.568

Genes affected

NWD1 (HGNC:27619): (NACHT and WD repeat domain containing 1) The protein encoded by this gene is thought to be a cytosolic protein and predicted to contain a NACHT domain and multiple WD40 repeats. Increased expression of this gene was observed in some prostate cancer cell lines. Knocking down expression of this gene results in decreased androgen receptor protein levels, indicating that this gene may be important in modulating androgen receptor activity. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Dec 2016]

NWD1 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3627097).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NWD1	NM_001007525.5	c.449G>T	p.Arg150Met	missense_variant	5/19	ENST00000524140.7	NP_001007526.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NWD1	ENST00000524140.7	c.449G>T	p.Arg150Met	missense_variant	5/19	1	NM_001007525.5	ENSP00000428579.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

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

Jul 12, 2022

The c.449G>T (p.R150M) alteration is located in exon 5 (coding exon 3) of the NWD1 gene. This alteration results from a G to T substitution at nucleotide position 449, causing the arginine (R) at amino acid position 150 to be replaced by a methionine (M). 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	0.21
BayesDel_addAF	Benign	-0.073	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	21
DANN	Benign	0.96
DEOGEN2	Benign	0.029	.;.;.;T
Eigen	Uncertain	0.32
Eigen_PC	Benign	0.22
FATHMM_MKL	Benign	0.49	N
LIST_S2	Benign	0.62	.;T;T;T
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.36	T;T;T;T
MetaSVM	Benign	-0.74	T
MutationAssessor	Uncertain	2.3	M;.;M;M
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-2.2	N;N;N;N
REVEL	Uncertain	0.31
Sift	Uncertain	0.012	D;D;D;D
Sift4G	Uncertain	0.0030	D;D;D;D
Polyphen		1.0	D;.;D;.
Vest4		0.43
MutPred		0.46		Loss of solvent accessibility (P = 0.0172);Loss of solvent accessibility (P = 0.0172);Loss of solvent accessibility (P = 0.0172);Loss of solvent accessibility (P = 0.0172);
MVP		0.41
MPC		0.57
ClinPred		0.92	D
GERP RS		3.2
Varity_R		0.15
gMVP		0.34

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: rs1568345079; hg19: chr19-16855482; COSMIC: COSV60345019;