rs75964850

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_025132.4(WDR19):c.910G>A(p.Val304Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0343 in 1,564,718 control chromosomes in the GnomAD database, including 1,050 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V304D) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.039 ( 133 hom., cov: 32)

Exomes 𝑓: 0.034 ( 917 hom. )

Consequence

WDR19
NM_025132.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: 0.242

Publications

10 publications found

Variant links:

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]

WDR19 Gene-Disease associations (from GenCC):

asphyxiating thoracic dystrophy 5
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
ciliopathy
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
cranioectodermal dysplasia 4
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
nephronophthisis 13
Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
Senior-Loken syndrome 8
Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
cranioectodermal dysplasia
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
Jeune syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
nephronophthisis 1
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
Senior-Loken syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

WDR19 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0018529892).

BP6

Variant 4-39214620-G-A is Benign according to our data. Variant chr4-39214620-G-A is described in ClinVar as Benign. ClinVar VariationId is 261868.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 = 0.0391 (5939/152004) while in subpopulation AFR AF = 0.0428 (1774/41452). AF 95% confidence interval is 0.0411. There are 133 homozygotes in GnomAd4. There are 2786 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 133 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_025132.4. 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
	WDR19	NM_025132.4	MANE Select	c.910G>A	p.Val304Ile	missense	Exon 10 of 37	NP_079408.3
	WDR19	NM_001317924.2		c.430G>A	p.Val144Ile	missense	Exon 9 of 36	NP_001304853.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
WDR19	ENST00000399820.8	TSL:1 MANE Select	c.910G>A	p.Val304Ile	missense	Exon 10 of 37	ENSP00000382717.3
WDR19	ENST00000503697.5	TSL:1	n.*378G>A		non_coding_transcript_exon	Exon 8 of 9	ENSP00000423706.1
WDR19	ENST00000503697.5	TSL:1	n.*378G>A		3_prime_UTR	Exon 8 of 9	ENSP00000423706.1

Frequencies

GnomAD3 genomes

AF:

0.0391

AC:

5932

AN:

151886

Hom.:

133

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0428

Gnomad AMI

AF:

0.00548

Gnomad AMR

AF:

0.0309

Gnomad ASJ

AF:

0.0631

Gnomad EAS

AF:

0.0129

Gnomad SAS

AF:

0.0338

Gnomad FIN

AF:

0.0279

Gnomad MID

AF:

0.0601

Gnomad NFE

AF:

0.0415

Gnomad OTH

AF:

0.0493

GnomAD2 exomes

AF:

0.0336

AC:

7829

AN:

232882

AF XY:

0.0336

show subpopulations

Gnomad AFR exome

AF:

0.0422

Gnomad AMR exome

AF:

0.0199

Gnomad ASJ exome

AF:

0.0646

Gnomad EAS exome

AF:

0.0112

Gnomad FIN exome

AF:

0.0251

Gnomad NFE exome

AF:

0.0400

Gnomad OTH exome

AF:

0.0395

GnomAD4 exome

AF:

0.0338

AC:

47715

AN:

1412714

Hom.:

917

Cov.:

AF XY:

0.0338

AC XY:

23752

AN XY:

702544

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0360

AC:

1149

AN:

31910

American (AMR)

AF:

0.0210

AC:

841

AN:

39956

Ashkenazi Jewish (ASJ)

AF:

0.0629

AC:

1591

AN:

25308

East Asian (EAS)

AF:

0.00954

AC:

374

AN:

39214

South Asian (SAS)

AF:

0.0261

AC:

2040

AN:

78306

European-Finnish (FIN)

AF:

0.0256

AC:

1355

AN:

52912

Middle Eastern (MID)

AF:

0.0594

AC:

335

AN:

5636

European-Non Finnish (NFE)

AF:

0.0351

AC:

37962

AN:

1080770

Other (OTH)

AF:

0.0352

AC:

2068

AN:

58702

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.393

Heterozygous variant carriers

1673

3345

5018

6690

8363

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1388

2776

4164

5552

6940

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0391

AC:

5939

AN:

152004

Hom.:

133

Cov.:

AF XY:

0.0375

AC XY:

2786

AN XY:

74260

show subpopulations

African (AFR)

AF:

0.0428

AC:

1774

AN:

41452

American (AMR)

AF:

0.0308

AC:

470

AN:

15236

Ashkenazi Jewish (ASJ)

AF:

0.0631

AC:

219

AN:

3472

East Asian (EAS)

AF:

0.0129

AC:

AN:

5174

South Asian (SAS)

AF:

0.0340

AC:

164

AN:

4820

European-Finnish (FIN)

AF:

0.0279

AC:

294

AN:

10546

Middle Eastern (MID)

AF:

0.0646

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0416

AC:

2825

AN:

67988

Other (OTH)

AF:

0.0483

AC:

102

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

284

568

853

1137

1421

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

140

210

280

350

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0411

Hom.:

304

Bravo

AF:

0.0390

TwinsUK

AF:

0.0402

AC:

149

ALSPAC

AF:

0.0402

AC:

155

ESP6500AA

AF:

0.0396

AC:

143

ESP6500EA

AF:

0.0435

AC:

354

ExAC

AF:

0.0342

AC:

4133

Asia WGS

AF:

0.0190

AC:

AN:

3478

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (3)

Asphyxiating thoracic dystrophy 5 (2)

Cranioectodermal dysplasia 4 (2)

not provided (2)

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

Connective tissue disorder (1)

Nephronophthisis 13 (1)

Senior-Loken syndrome 8 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.072

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.32

CADD

Benign

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.098

Eigen

Benign

-0.46

Eigen_PC

Benign

-0.34

FATHMM_MKL

Benign

0.71

LIST_S2

Uncertain

0.91

MetaRNN

Benign

0.0019

MetaSVM

Benign

-0.41

MutationAssessor

Benign

0.55

PhyloP100

0.24

PrimateAI

Benign

0.28

PROVEAN

Benign

-0.40

REVEL

Benign

0.11

Sift

Benign

0.26

Sift4G

Benign

0.092

Polyphen

0.0040

Vest4

0.094

MPC

0.15

ClinPred

0.0049

GERP RS

0.086

Varity_R

0.019

gMVP

0.097

Mutation Taster

=98/2

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over