rs14398

Variant names:

• chr6-33286888-A-G
• rs14398
• NM_005452.6:c.1022T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_005452.6(WDR46):​c.1022T>C​(p.Val341Ala) variant causes a missense change. The variant allele was found at a frequency of 0.134 in 1,613,936 control chromosomes in the GnomAD database, including 15,849 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.10 (995 hom., cov: 31)
  • Exomes 𝑓: 0.14 (14854 hom.)
• Consequence: WDR46 NM_005452.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.17
• Publications: 38 publications found

Genes affected

WDR46 (HGNC:13923): (WD repeat domain 46) Enables RNA binding activity. Predicted to be involved in maturation of SSU-rRNA from tricistronic rRNA transcript (SSU-rRNA, 5.8S rRNA, LSU-rRNA). Predicted to be located in nucleoplasm. Predicted to be part of small-subunit processome. Predicted to be active in nucleolus. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0017456114).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.187 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WDR46	NM_005452.6	c.1022T>C	p.Val341Ala	missense_variant	Exon 10 of 15	ENST00000374617.9	NP_005443.3
WDR46	NM_001164267.2	c.860T>C	p.Val287Ala	missense_variant	Exon 10 of 15		NP_001157739.1
WDR46	XM_047419523.1	c.1022T>C	p.Val341Ala	missense_variant	Exon 10 of 14		XP_047275479.1
WDR46	XM_047419524.1	c.1022T>C	p.Val341Ala	missense_variant	Exon 10 of 11		XP_047275480.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WDR46	ENST00000374617.9	c.1022T>C	p.Val341Ala	missense_variant	Exon 10 of 15	1	NM_005452.6	ENSP00000363746.4
WDR46	ENST00000444176.1	c.803T>C	p.Val268Ala	missense_variant	Exon 9 of 10	5		ENSP00000405568.1
WDR46	ENST00000489905.1	n.218T>C		non_coding_transcript_exon_variant	Exon 3 of 6	5

Frequencies

GnomAD3 genomes AF: 0.100 AC: 15243 AN: 152132 Hom.: 990 Cov.: 31

Gnomad AFR AF: 0.0251

Gnomad AMI AF: 0.117

Gnomad AMR AF: 0.105

Gnomad ASJ AF: 0.208

Gnomad EAS AF: 0.0723

Gnomad SAS AF: 0.197

Gnomad FIN AF: 0.0781

Gnomad MID AF: 0.180

Gnomad NFE AF: 0.136

Gnomad OTH AF: 0.135

GnomAD2 exomes AF: 0.124 AC: 31139 AN: 250992 AF XY: 0.132

Gnomad AFR exome AF: 0.0225

Gnomad AMR exome AF: 0.0772

Gnomad ASJ exome AF: 0.214

Gnomad EAS exome AF: 0.0634

Gnomad FIN exome AF: 0.0798

Gnomad NFE exome AF: 0.141

Gnomad OTH exome AF: 0.152

GnomAD4 exome AF: 0.137 AC: 200883 AN: 1461686 Hom.: 14854 Cov.: 35 AF XY: 0.140 AC XY: 101825 AN XY: 727170

African (AFR) AF: 0.0208 AC: 698 AN: 33478

American (AMR) AF: 0.0812 AC: 3631 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.214 AC: 5600 AN: 26136

East Asian (EAS) AF: 0.0622 AC: 2469 AN: 39700

South Asian (SAS) AF: 0.203 AC: 17478 AN: 86244

European-Finnish (FIN) AF: 0.0840 AC: 4486 AN: 53406

Middle Eastern (MID) AF: 0.185 AC: 1067 AN: 5768

European-Non Finnish (NFE) AF: 0.141 AC: 156710 AN: 1111854

Other (OTH) AF: 0.145 AC: 8744 AN: 60384

GnomAD4 genome AF: 0.100 AC: 15258 AN: 152250 Hom.: 995 Cov.: 31 AF XY: 0.0996 AC XY: 7411 AN XY: 74432

African (AFR) AF: 0.0250 AC: 1041 AN: 41564

American (AMR) AF: 0.105 AC: 1603 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.208 AC: 722 AN: 3472

East Asian (EAS) AF: 0.0725 AC: 375 AN: 5174

South Asian (SAS) AF: 0.197 AC: 951 AN: 4818

European-Finnish (FIN) AF: 0.0781 AC: 828 AN: 10606

Middle Eastern (MID) AF: 0.184 AC: 54 AN: 294

European-Non Finnish (NFE) AF: 0.137 AC: 9284 AN: 68006

Other (OTH) AF: 0.139 AC: 293 AN: 2114

Alfa AF: 0.128 Hom.: 4504

Bravo AF: 0.0979

TwinsUK AF: 0.152 AC: 565

ALSPAC AF: 0.144 AC: 555

ESP6500AA AF: 0.0295 AC: 130

ESP6500EA AF: 0.144 AC: 1237

ExAC AF: 0.125 AC: 15178

Asia WGS AF: 0.157 AC: 545 AN: 3478

EpiCase AF: 0.148

EpiControl AF: 0.146

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.73
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.11
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.29	T;.
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.67	T;T
MetaRNN	Benign	0.0017	T;T
MetaSVM	Benign	-0.64	T
MutationAssessor	Pathogenic	3.4	M;.
PhyloP100		7.2
PrimateAI	Uncertain	0.64	T
PROVEAN	Uncertain	-3.9	D;D
REVEL	Uncertain	0.35
Sift	Uncertain	0.0060	D;D
Sift4G	Uncertain	0.0040	D;.
Polyphen		1.0	D;.
Vest4		0.28
MPC		1.1
ClinPred		0.028	T
GERP RS		4.8
Varity_R		0.46
gMVP		0.74
Mutation Taster		=71/29	polymorphism (auto)

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: rs14398; hg19: chr6-33254665;