4-39253208-A-C

Position:

• chr4-39253208-A-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_025132.4(WDR19):​c.2792A>C​(p.Tyr931Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0056 in 1,613,688 control chromosomes in the GnomAD database, including 31 homozygotes. 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0026 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0059 (31 hom.)
• Consequence: WDR19 NM_025132.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:8
• Conservation: PhyloP100: 3.81

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.022140175).
• BP6: Variant 4-39253208-A-C is Benign according to our data. Variant chr4-39253208-A-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 167843.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=4, Benign=1}. Variant chr4-39253208-A-C is described in Lovd as [Benign]. Variant chr4-39253208-A-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00259 (394/152330) while in subpopulation NFE AF= 0.00492 (335/68036). AF 95% confidence interval is 0.00449. There are 0 homozygotes in gnomad4. There are 163 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 31 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WDR19	NM_025132.4	c.2792A>C	p.Tyr931Ser	missense_variant	25/37	ENST00000399820.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WDR19	ENST00000399820.8	c.2792A>C	p.Tyr931Ser	missense_variant	25/37	1	NM_025132.4	P1
WDR19	ENST00000512095.5	n.1790A>C		non_coding_transcript_exon_variant	15/23	2
WDR19	ENST00000506869.5	c.*2373A>C		3_prime_UTR_variant, NMD_transcript_variant	24/36	2

Frequencies

GnomAD3 genomes AF: 0.00259 AC: 394 AN: 152212 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000892

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000851

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00492

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00279 AC: 695 AN: 248780 Hom.: 1 AF XY: 0.00282 AC XY: 380 AN XY: 134958

Gnomad AFR exome AF: 0.00110

Gnomad AMR exome AF: 0.000524

Gnomad ASJ exome AF: 0.0000995

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00107

Gnomad NFE exome AF: 0.00550

Gnomad OTH exome AF: 0.00265

GnomAD4 exome AF: 0.00592 AC: 8650 AN: 1461358 Hom.: 31 Cov.: 31 AF XY: 0.00572 AC XY: 4156 AN XY: 726944

Gnomad4 AFR exome AF: 0.000777

Gnomad4 AMR exome AF: 0.000627

Gnomad4 ASJ exome AF: 0.000153

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.000937

Gnomad4 NFE exome AF: 0.00754

Gnomad4 OTH exome AF: 0.00255

GnomAD4 genome AF: 0.00259 AC: 394 AN: 152330 Hom.: 0 Cov.: 31 AF XY: 0.00219 AC XY: 163 AN XY: 74486

Gnomad4 AFR AF: 0.000890

Gnomad4 AMR AF: 0.000850

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000283

Gnomad4 NFE AF: 0.00492

Gnomad4 OTH AF: 0.00236

Alfa AF: 0.00476 Hom.: 10

Bravo AF: 0.00278

TwinsUK AF: 0.00728 AC: 27

ALSPAC AF: 0.00675 AC: 26

ESP6500AA AF: 0.00109 AC: 4

ESP6500EA AF: 0.00561 AC: 46

ExAC AF: 0.00265 AC: 320

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00475

EpiControl AF: 0.00516

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:8

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:2

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 03, 2014	- -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 12, 2023	The WDR19 c.2792A>C; p.Tyr931Ser variant (rs187546086), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 167843). This variant is found in the general population with an overall allele frequency of 0.27% (768/280184 alleles, including a single homozygote) in the Genome Aggregation Database. The tyrosine at codon 931 is weakly conserved, and computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.308). Due to limited information, the clinical significance of the p.Tyr931Ser variant is uncertain at this time. -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Oct 15, 2015	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 18, 2022

The c.2792A>C (p.Y931S) alteration is located in exon 25 (coding exon 25) of the WDR19 gene. This alteration results from a A to C substitution at nucleotide position 2792, causing the tyrosine (Y) at amino acid position 931 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Connective tissue disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Mar 01, 2021

- -

Asphyxiating thoracic dystrophy 5 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

WDR19-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 17, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Cranioectodermal dysplasia 4 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	20
DANN	Benign	0.94
DEOGEN2	Benign	0.24	T
Eigen	Benign	-0.16
Eigen_PC	Benign	0.052
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.022	T
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	1.6	L
MutationTaster	Benign	0.96	D;D
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-2.0	N
REVEL	Uncertain	0.31
Sift	Benign	0.39	T
Sift4G	Benign	0.39	T
Polyphen		0.010	B
Vest4		0.71
MVP		0.76
MPC		0.24
ClinPred		0.027	T
GERP RS		5.5
Varity_R		0.15
gMVP		0.59

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: rs187546086; hg19: chr4-39254828; COSMIC: COSV56470385;