6-33287326-A-C

Variant names:

• chr6-33287326-A-C
• rs446735
• NM_005452.6:c.879+29T>G

Variant summary

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

The NM_005452.6(WDR46):​c.879+29T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.541 in 1,611,646 control chromosomes in the GnomAD database, including 238,963 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 0.59 (27002 hom., cov: 27)
  • Exomes 𝑓: 0.54 (211961 hom.)
• Consequence: WDR46 NM_005452.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.314
• Publications: 20 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]

MIR6873 (HGNC:50231): (microRNA 6873) microRNAs (miRNAs) are short (20-24 nt) non-coding RNAs that are involved in post-transcriptional regulation of gene expression in multicellular organisms by affecting both the stability and translation of mRNAs. miRNAs are transcribed by RNA polymerase II as part of capped and polyadenylated primary transcripts (pri-miRNAs) that can be either protein-coding or non-coding. The primary transcript is cleaved by the Drosha ribonuclease III enzyme to produce an approximately 70-nt stem-loop precursor miRNA (pre-miRNA), which is further cleaved by the cytoplasmic Dicer ribonuclease to generate the mature miRNA and antisense miRNA star (miRNA*) products. The mature miRNA is incorporated into a RNA-induced silencing complex (RISC), which recognizes target mRNAs through imperfect base pairing with the miRNA and most commonly results in translational inhibition or destabilization of the target mRNA. The RefSeq represents the predicted microRNA stem-loop. [provided by RefSeq, Sep 2009]

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.73 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005452.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WDR46	NM_005452.6	MANE Select	c.879+29T>G		intron	N/A	NP_005443.3
	WDR46	NM_001164267.2		c.717+29T>G		intron	N/A	NP_001157739.1
	MIR6873	NR_106933.1		n.-37T>G		upstream_gene	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WDR46	ENST00000374617.9	TSL:1 MANE Select	c.879+29T>G		intron	N/A	ENSP00000363746.4
	WDR46	ENST00000488944.5	TSL:3	n.455T>G		non_coding_transcript_exon	Exon 2 of 2
	WDR46	ENST00000444176.1	TSL:5	c.660+29T>G		intron	N/A	ENSP00000405568.1

Frequencies

GnomAD3 genomes AF: 0.591 AC: 88759 AN: 150064 Hom.: 26949 Cov.: 27

Gnomad AFR AF: 0.736

Gnomad AMI AF: 0.387

Gnomad AMR AF: 0.579

Gnomad ASJ AF: 0.608

Gnomad EAS AF: 0.391

Gnomad SAS AF: 0.619

Gnomad FIN AF: 0.525

Gnomad MID AF: 0.580

Gnomad NFE AF: 0.532

Gnomad OTH AF: 0.590

GnomAD2 exomes AF: 0.555 AC: 139269 AN: 251104 AF XY: 0.557

Gnomad AFR exome AF: 0.751

Gnomad AMR exome AF: 0.534

Gnomad ASJ exome AF: 0.597

Gnomad EAS exome AF: 0.368

Gnomad FIN exome AF: 0.528

Gnomad NFE exome AF: 0.544

Gnomad OTH exome AF: 0.569

GnomAD4 exome AF: 0.535 AC: 782290 AN: 1461464 Hom.: 211961 Cov.: 67 AF XY: 0.539 AC XY: 391493 AN XY: 726936

African (AFR) AF: 0.747 AC: 24996 AN: 33464

American (AMR) AF: 0.538 AC: 24060 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.599 AC: 15643 AN: 26128

East Asian (EAS) AF: 0.350 AC: 13900 AN: 39692

South Asian (SAS) AF: 0.626 AC: 53970 AN: 86254

European-Finnish (FIN) AF: 0.529 AC: 28231 AN: 53416

Middle Eastern (MID) AF: 0.580 AC: 3342 AN: 5766

European-Non Finnish (NFE) AF: 0.526 AC: 584504 AN: 1111658

Other (OTH) AF: 0.557 AC: 33644 AN: 60376

GnomAD4 genome AF: 0.592 AC: 88865 AN: 150182 Hom.: 27002 Cov.: 27 AF XY: 0.592 AC XY: 43281 AN XY: 73150

African (AFR) AF: 0.737 AC: 30073 AN: 40802

American (AMR) AF: 0.578 AC: 8671 AN: 14990

Ashkenazi Jewish (ASJ) AF: 0.608 AC: 2105 AN: 3462

East Asian (EAS) AF: 0.391 AC: 1984 AN: 5080

South Asian (SAS) AF: 0.619 AC: 2828 AN: 4566

European-Finnish (FIN) AF: 0.525 AC: 5431 AN: 10340

Middle Eastern (MID) AF: 0.572 AC: 167 AN: 292

European-Non Finnish (NFE) AF: 0.533 AC: 36048 AN: 67690

Other (OTH) AF: 0.587 AC: 1210 AN: 2060

Alfa AF: 0.563 Hom.: 30329

Bravo AF: 0.600

Asia WGS AF: 0.514 AC: 1789 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	6.4
DANN	Benign	0.70
PhyloP100		-0.31
Mutation Taster		=100/0	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: rs446735; hg19: chr6-33255103; COSMIC: COSV65842285; COSMIC: COSV65842285;