rs17584431

Positions:

• chr4-39205698-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_025132.4(WDR19):​c.852A>G​(p.Ser284=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.152 in 1,608,074 control chromosomes in the GnomAD database, including 19,782 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.12 (1330 hom., cov: 32)
  • Exomes 𝑓: 0.16 (18452 hom.)
• Consequence: WDR19 NM_025132.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 0.250

Genes affected

WDR19 (HGNC:18340): (WD repeat domain 19) The protein encoded by this gene is a member of the WD (tryptophan-aspartic acid) repeat family, which is a large family of structurally-related proteins known to participate in a wide range of cellular processes. Each WD repeat typically contains about 40 amino acids that are usually bracketed by glycine-histidine and tryptophan-aspartic acid (WD) dipeptides. This protein contains six WD repeats, three transmembrane domains, and a clathrin heavy-chain repeat. Mutations in this gene have been described in individuals with a wide range of disorders affecting function of the cilium. These disorders are known as ciliopathies, and include Jeune syndrome, Sensenbrenner syndromes, Senior-Loken syndrome, combined or isolated nephronophthisis (NPHP), and retinitis pigmentosa (RP). Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Dec 2015]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.51).
• BP6: Variant 4-39205698-A-G is Benign according to our data. Variant chr4-39205698-A-G is described in ClinVar as [Benign]. Clinvar id is 261866.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-39205698-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.25 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.202 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WDR19	NM_025132.4	c.852A>G	p.Ser284=	synonymous_variant	9/37	ENST00000399820.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WDR19	ENST00000399820.8	c.852A>G	p.Ser284=	synonymous_variant	9/37	1	NM_025132.4	P1

Frequencies

GnomAD3 genomes AF: 0.120 AC: 18279 AN: 152088 Hom.: 1328 Cov.: 32

Gnomad AFR AF: 0.0288

Gnomad AMI AF: 0.158

Gnomad AMR AF: 0.149

Gnomad ASJ AF: 0.131

Gnomad EAS AF: 0.154

Gnomad SAS AF: 0.212

Gnomad FIN AF: 0.172

Gnomad MID AF: 0.0981

Gnomad NFE AF: 0.151

Gnomad OTH AF: 0.125

GnomAD3 exomes AF: 0.158 AC: 37919 AN: 239844 Hom.: 3193 AF XY: 0.164 AC XY: 21251 AN XY: 129798

Gnomad AFR exome AF: 0.0224

Gnomad AMR exome AF: 0.170

Gnomad ASJ exome AF: 0.124

Gnomad EAS exome AF: 0.146

Gnomad SAS exome AF: 0.235

Gnomad FIN exome AF: 0.176

Gnomad NFE exome AF: 0.155

Gnomad OTH exome AF: 0.144

GnomAD4 exome AF: 0.155 AC: 226237 AN: 1455868 Hom.: 18452 Cov.: 32 AF XY: 0.158 AC XY: 114513 AN XY: 723626

Gnomad4 AFR exome AF: 0.0250

Gnomad4 AMR exome AF: 0.168

Gnomad4 ASJ exome AF: 0.123

Gnomad4 EAS exome AF: 0.166

Gnomad4 SAS exome AF: 0.231

Gnomad4 FIN exome AF: 0.172

Gnomad4 NFE exome AF: 0.153

Gnomad4 OTH exome AF: 0.152

GnomAD4 genome AF: 0.120 AC: 18280 AN: 152206 Hom.: 1330 Cov.: 32 AF XY: 0.123 AC XY: 9182 AN XY: 74408

Gnomad4 AFR AF: 0.0287

Gnomad4 AMR AF: 0.149

Gnomad4 ASJ AF: 0.131

Gnomad4 EAS AF: 0.154

Gnomad4 SAS AF: 0.213

Gnomad4 FIN AF: 0.172

Gnomad4 NFE AF: 0.151

Gnomad4 OTH AF: 0.124

Alfa AF: 0.147 Hom.: 2903

Bravo AF: 0.115

Asia WGS AF: 0.168 AC: 584 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Asphyxiating thoracic dystrophy 5 Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Dec 05, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 05, 2021	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Cranioectodermal dysplasia 4 Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Dec 05, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Nephronophthisis 13 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Dec 05, 2021

- -

Senior-Loken syndrome 8 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Dec 05, 2021

- -

Asphyxiating thoracic dystrophy 5;C4225376:Senior-Loken syndrome 8 Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
CADD	Benign	8.3
DANN	Benign	0.67

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: rs17584431; hg19: chr4-39207318; COSMIC: COSV56468473; COSMIC: COSV56468473;