2-28894833-C-A

Position:

• chr2-28894833-C-A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_015131.3(WDR43):​c.135C>A​(p.Asn45Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000411 in 1,458,892 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: not found (cov: 33)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: WDR43 NM_015131.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.74

Genes affected

WDR43 (HGNC:28945): (WD repeat domain 43) Enables RNA binding activity. Involved in positive regulation of rRNA processing and positive regulation of transcription by RNA polymerase I. Located in fibrillar center. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.18656898).
• BS2: High AC in GnomAdExome4 at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
WDR43	NM_015131.3	c.135C>A	p.Asn45Lys	missense_variant	1/18	ENST00000407426.8	NP_055946.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
WDR43	ENST00000407426.8	c.135C>A	p.Asn45Lys	missense_variant	1/18	1	NM_015131.3	ENSP00000384302.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000411 AC: 6 AN: 1458892 Hom.: 0 Cov.: 31 AF XY: 0.00000551 AC XY: 4 AN XY: 725598

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.00000540

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

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

Aug 27, 2024

The c.135C>A (p.N45K) alteration is located in exon 1 (coding exon 1) of the WDR43 gene. This alteration results from a C to A substitution at nucleotide position 135, causing the asparagine (N) at amino acid position 45 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	0.18
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	20
DANN	Uncertain	0.98
DEOGEN2	Benign	0.057	T
Eigen	Benign	-0.41
Eigen_PC	Benign	-0.29
FATHMM_MKL	Benign	0.73	D
LIST_S2	Benign	0.64	T
M_CAP	Uncertain	0.090	D
MetaRNN	Benign	0.19	T
MetaSVM	Benign	-0.87	T
MutationAssessor	Benign	1.1	L
PrimateAI	Pathogenic	0.80	T
PROVEAN	Benign	-2.3	N
REVEL	Benign	0.11
Sift	Benign	0.043	D
Sift4G	Uncertain	0.027	D
Polyphen		0.10	B
Vest4		0.26
MutPred		0.50		Gain of ubiquitination at N45 (P = 0.0247);
MVP		0.25
MPC		0.20
ClinPred		0.65	D
GERP RS		3.9
Varity_R		0.21
gMVP		0.28

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-29117699; COSMIC: COSV68019277; COSMIC: COSV68019277;