rs541910371

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2PP3_StrongPP5

The NM_020779.4(WDR35):​c.3170A>G​(p.Tyr1057Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000929 in 1,613,858 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000075 ( 0 hom. )

Consequence

WDR35
NM_020779.4 missense

Scores

11
6
2

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3U:2

Conservation

PhyloP100: 7.61
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.967
PP5
Variant 2-19914229-T-C is Pathogenic according to our data. Variant chr2-19914229-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 440412.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Uncertain_significance=2}.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
WDR35NM_001006657.2 linkc.3203A>G p.Tyr1068Cys missense_variant Exon 27 of 28 ENST00000345530.8 NP_001006658.1 Q9P2L0-1
WDR35NM_020779.4 linkc.3170A>G p.Tyr1057Cys missense_variant Exon 26 of 27 ENST00000281405.9 NP_065830.2 Q9P2L0-2
WDR35XM_011533007.3 linkc.1898A>G p.Tyr633Cys missense_variant Exon 16 of 17 XP_011531309.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
WDR35ENST00000345530.8 linkc.3203A>G p.Tyr1068Cys missense_variant Exon 27 of 28 1 NM_001006657.2 ENSP00000314444.5 Q9P2L0-1
WDR35ENST00000281405.9 linkc.3170A>G p.Tyr1057Cys missense_variant Exon 26 of 27 1 NM_020779.4 ENSP00000281405.5 Q9P2L0-2

Frequencies

GnomAD3 genomes
AF:
0.0000263
AC:
4
AN:
152014
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000483
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
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:
0.0000294
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000796
AC:
2
AN:
251262
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
135872
show subpopulations
Gnomad AFR exome
AF:
0.000124
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000752
AC:
11
AN:
1461844
Hom.:
0
Cov.:
31
AF XY:
0.00000413
AC XY:
3
AN XY:
727222
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000899
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.0000263
AC:
4
AN:
152014
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74276
show subpopulations
Gnomad4 AFR
AF:
0.0000483
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000294
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000648
Hom.:
0
Bravo
AF:
0.0000302
ExAC
AF:
0.00000824
AC:
1

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:3Uncertain:2
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Cranioectodermal dysplasia 2 Pathogenic:1Uncertain:1
Sep 01, 2017
Baylor Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant was previously reported as pathogenic and was found once in our laboratory In trans with another missense variant (H1031Y) in a 6-month-old male with cranioectodermal dysplasia. Heterozygotes would be expected to be asymptomatic carriers. -

Feb 06, 2018
OMIM
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: literature only

- -

not specified Pathogenic:1
Jan 17, 2017
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Inborn genetic diseases Pathogenic:1
Oct 31, 2023
Ambry Genetics
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.3203A>G (p.Y1068C) alteration is located in coding exon 27 of the WDR35 gene. This alteration results from an A to G substitution at nucleotide position 3203, causing the tyrosine (Y) at amino acid position 1068 to be replaced by a cysteine (C). Based on data from gnomAD, the G allele has an overall frequency of 0.001% (2/251262) total alleles studied. The highest observed frequency was 0.012% (2/16148) of African alleles. This variant has been reported as a compound heterozygous finding in trans in a child diagnosed with cranioectodermal dysplasia/Sensenbrenner syndrome (Lin, 2013; Li, 2023). This has also been prenatally detected as a compound heterozygous finding in a male fetus with hydrops and polyhydramnios on ultrasound (Walczak-Sztulpa, 2020). This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as likely pathogenic. -

Cranioectodermal dysplasia 2;C3279792:Short-rib thoracic dysplasia 7 with or without polydactyly Uncertain:1
Apr 24, 2024
Fulgent Genetics, Fulgent Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.17
BayesDel_addAF
Pathogenic
0.23
D
BayesDel_noAF
Pathogenic
0.32
CADD
Pathogenic
27
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.48
.;T
Eigen
Pathogenic
0.90
Eigen_PC
Pathogenic
0.84
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.97
D;D
M_CAP
Uncertain
0.23
D
MetaRNN
Pathogenic
0.97
D;D
MetaSVM
Uncertain
0.37
D
MutationAssessor
Pathogenic
3.2
.;M
PrimateAI
Uncertain
0.77
T
PROVEAN
Pathogenic
-8.6
D;D
REVEL
Pathogenic
0.85
Sift
Pathogenic
0.0
D;D
Sift4G
Pathogenic
0.0010
D;D
Polyphen
1.0
D;D
Vest4
0.99
MVP
0.87
MPC
0.62
ClinPred
1.0
D
GERP RS
5.5
Varity_R
0.88
gMVP
0.80

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.030
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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs541910371; hg19: chr2-20113990; API