19-12669899-C-T

Position:

• chr19-12669899-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001099737.3(WDR83):​c.103+6C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00202 in 1,603,658 control chromosomes in the GnomAD database, including 46 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (25 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (21 hom.)
• Consequence: WDR83 NM_001099737.3 splice_region, intron
• Scores: Splicing: ADA: 0.0002259
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.00300

Genes affected

WDR83 (HGNC:32672): (WD repeat domain 83) This gene encodes a member of the WD-40 protein family. The protein is proposed to function as a molecular scaffold for various multimeric protein complexes. The protein associates with several components of the extracellular signal-regulated kinase (ERK) pathway, and promotes ERK activity in response to serum or other signals. The protein also interacts with egl nine homolog 3 (EGLN3, also known as PHD3) and regulates expression of hypoxia-inducible factor 1, and has been purified as part of the spliceosome. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Oct 2009]

ENSG00000285589 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).
• BP6: Variant 19-12669899-C-T is Benign according to our data. Variant chr19-12669899-C-T is described in ClinVar as [Benign]. Clinvar id is 777522.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0105 (1606/152310) while in subpopulation AFR AF= 0.0365 (1516/41568). AF 95% confidence interval is 0.0349. There are 25 homozygotes in gnomad4. There are 764 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 25 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
WDR83	NM_001099737.3	c.103+6C>T		splice_region_variant, intron_variant		ENST00000418543.8	NP_001093207.1
WDR83	NM_032332.4	c.103+6C>T		splice_region_variant, intron_variant			NP_115708.1
WDR83	NR_029375.2	n.445+6C>T		splice_region_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
WDR83	ENST00000418543.8	c.103+6C>T		splice_region_variant, intron_variant		1	NM_001099737.3	ENSP00000402653.3
ENSG00000285589	ENST00000648033.1	n.*3439G>A		non_coding_transcript_exon_variant	11/14			ENSP00000498000.1
ENSG00000285589	ENST00000648033.1	n.*3439G>A		3_prime_UTR_variant	11/14			ENSP00000498000.1

Frequencies

GnomAD3 genomes AF: 0.0105 AC: 1605 AN: 152192 Hom.: 25 Cov.: 32

Gnomad AFR AF: 0.0365

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00406

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.00861

GnomAD3 exomes AF: 0.00289 AC: 714 AN: 247328 Hom.: 10 AF XY: 0.00200 AC XY: 268 AN XY: 133808

Gnomad AFR exome AF: 0.0367

Gnomad AMR exome AF: 0.00274

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000932

Gnomad NFE exome AF: 0.000125

Gnomad OTH exome AF: 0.00199

GnomAD4 exome AF: 0.00112 AC: 1627 AN: 1451348 Hom.: 21 Cov.: 31 AF XY: 0.000969 AC XY: 698 AN XY: 720060

Gnomad4 AFR exome AF: 0.0368

Gnomad4 AMR exome AF: 0.00274

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000584

Gnomad4 FIN exome AF: 0.000189

Gnomad4 NFE exome AF: 0.000110

Gnomad4 OTH exome AF: 0.00229

GnomAD4 genome AF: 0.0105 AC: 1606 AN: 152310 Hom.: 25 Cov.: 32 AF XY: 0.0103 AC XY: 764 AN XY: 74478

Gnomad4 AFR AF: 0.0365

Gnomad4 AMR AF: 0.00405

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000147

Gnomad4 OTH AF: 0.00852

Alfa AF: 0.00504 Hom.: 1

Bravo AF: 0.0119

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	May 08, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	12
DANN	Benign	0.90

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00023
dbscSNV1_RF	Benign	0.0080
SpliceAI score (max)		0.020		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: rs116778851; hg19: chr19-12780713;