2-19937861-T-C

Variant names:

Variant summary

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

The NM_001006657.2(WDR35):c.2182A>G(p.Ile728Val) variant causes a missense change. The variant allele was found at a frequency of 0.00113 in 1,614,166 control chromosomes in the GnomAD database, including 32 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I728L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0029 ( 8 hom., cov: 32)

Exomes 𝑓: 0.00094 ( 24 hom. )

Consequence

WDR35
NM_001006657.2 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 6.10

Publications

3 publications found

Variant links:

Genes affected

WDR35 (HGNC:29250): (WD repeat domain 35) This gene encodes a member of the WD repeat protein family. WD repeats are minimally conserved regions of approximately 40 amino acids typically bracketed by gly-his and trp-asp (GH-WD), which may facilitate formation of heterotrimeric or multiprotein complexes. Members of this family are involved in a variety of cellular processes, including cell cycle progression, signal transduction, apoptosis, and gene regulation. Multiple alternatively spliced transcript variants encoding distinct isoforms have been found for this gene. Two patients with Sensenbrenner syndrome / cranioectodermal dysplasia (CED) were identified with mutations in this gene, consistent with a possible ciliary function.[provided by RefSeq, Sep 2010]

WDR35 Gene-Disease associations (from GenCC):

cranioectodermal dysplasia 2
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, PanelApp Australia, ClinGen, Ambry Genetics
short-rib thoracic dysplasia 7 with or without polydactyly
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Orphanet, Labcorp Genetics (formerly Invitae)
cranioectodermal dysplasia
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
short rib-polydactyly syndrome, Verma-Naumoff type
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

WDR35 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=0.008346021).

BP6

Variant 2-19937861-T-C is Benign according to our data. Variant chr2-19937861-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 195468.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00291 (443/152316) while in subpopulation AMR AF = 0.0282 (431/15292). AF 95% confidence interval is 0.026. There are 8 homozygotes in GnomAd4. There are 275 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WDR35	NM_001006657.2 link	c.2182A>G	p.Ile728Val	missense_variant	Exon 20 of 28	ENST00000345530.8	NP_001006658.1
WDR35	NM_020779.4 link	c.2149A>G	p.Ile717Val	missense_variant	Exon 19 of 27	ENST00000281405.9	NP_065830.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WDR35	ENST00000345530.8 link	c.2182A>G	p.Ile728Val	missense_variant	Exon 20 of 28	1	NM_001006657.2	ENSP00000314444.5
WDR35	ENST00000281405.9 link	c.2149A>G	p.Ile717Val	missense_variant	Exon 19 of 27	1	NM_020779.4	ENSP00000281405.5

Frequencies

GnomAD3 genomes

AF:

0.00291

AC:

443

AN:

152198

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0282

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00143

GnomAD2 exomes

AF:

0.00471

AC:

1184

AN:

251302

AF XY:

0.00349

show subpopulations

Gnomad AFR exome

AF:

0.000308

Gnomad AMR exome

AF:

0.0335

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00293

GnomAD4 exome

AF:

0.000944

AC:

1380

AN:

1461850

Hom.:

Cov.:

AF XY:

0.000778

AC XY:

566

AN XY:

727224

show subpopulations

African (AFR)

AF:

0.000149

AC:

AN:

33478

American (AMR)

AF:

0.0300

AC:

1343

AN:

44706

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39696

South Asian (SAS)

AF:

0.00

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000360

AC:

AN:

1111994

Other (OTH)

AF:

0.000464

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

112

224

337

449

561

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

<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:

0.00291

AC:

443

AN:

152316

Hom.:

Cov.:

AF XY:

0.00369

AC XY:

275

AN XY:

74488

show subpopulations

African (AFR)

AF:

0.000120

AC:

AN:

41586

American (AMR)

AF:

0.0282

AC:

431

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000588

AC:

AN:

68012

Other (OTH)

AF:

0.00142

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

118

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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:

0.000549

Hom.:

Bravo

AF:

0.00367

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.00346

AC:

420

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Aug 27, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 06, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cranioectodermal dysplasia 2;C3279792:Short-rib thoracic dysplasia 7 with or without polydactyly

Benign:2

Oct 18, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

May 11, 2015

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

WDR35-related disorder

Benign:1

May 14, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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

Cranioectodermal dysplasia 2

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Short-rib thoracic dysplasia 7 with or without polydactyly

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.16

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.049

.;T;.

Eigen

Uncertain

0.43

Eigen_PC

Uncertain

0.47

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.96

D;D;D

MetaRNN

Benign

0.0083

T;T;T

MetaSVM

Uncertain

0.095

MutationAssessor

Uncertain

2.0

.;M;.

PhyloP100

6.1

PrimateAI

Uncertain

0.54

PROVEAN

Benign

-0.87

N;N;N

REVEL

Uncertain

0.38

Sift

Benign

0.059

T;T;T

Sift4G

Benign

0.12

T;T;T

Polyphen

0.93

P;P;.

Vest4

0.50

MVP

0.61

MPC

0.48

ClinPred

0.023

GERP RS

5.2

Varity_R

0.17

gMVP

0.34

Mutation Taster

=95/5

polymorphism

(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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over