4-37245162-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_001144990.2(NWD2):c.95C>T(p.Ser32Phe) variant causes a missense change. The variant allele was found at a frequency of 0.00000574 in 1,394,310 control chromosomes in the GnomAD database, including 1 homozygotes. 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)
  • Exomes 𝑓: 0.0000057 (1 hom.)
• Consequence: NWD2 NM_001144990.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.00

Genes affected

NWD2 (HGNC:29229): (NACHT and WD repeat domain containing 2)

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, NWD2
• BP4: Computational evidence support a benign effect (MetaRNN=0.1313588).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NWD2	NM_001144990.2	c.95C>T	p.Ser32Phe	missense_variant	1/7	ENST00000309447.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NWD2	ENST00000309447.6	c.95C>T	p.Ser32Phe	missense_variant	1/7	5	NM_001144990.2	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000423 AC: 6 AN: 141758 Hom.: 1 AF XY: 0.0000782 AC XY: 6 AN XY: 76698

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000246

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

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: 0.00000574 AC: 8 AN: 1394310 Hom.: 1 Cov.: 32 AF XY: 0.00000872 AC XY: 6 AN XY: 687868

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000225

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

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

Nov 27, 2023

The c.95C>T (p.S32F) alteration is located in exon 1 (coding exon 1) of the NWD2 gene. This alteration results from a C to T substitution at nucleotide position 95, causing the serine (S) at amino acid position 32 to be replaced by a phenylalanine (F). 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	0.13
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.55
Cadd	Uncertain	23
Dann	Uncertain	1.0
DEOGEN2	Benign	0.026	T
Eigen	Benign	0.064
Eigen_PC	Benign	0.22
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.83	T
M_CAP	Benign	0.043	D
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.90	L
MutationTaster	Benign	0.60	D
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.058
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.012	D
Polyphen		0.14	B
Vest4		0.22
MutPred		0.37		Loss of disorder (P = 0.0196);
MVP		0.11
ClinPred		0.16	T
GERP RS		4.8
Varity_R		0.25
gMVP		0.29

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: rs1048096970; hg19: chr4-37246784;