rs200140363

chr2-19953852-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM2 PP5_Moderate BP4

The NM_001006657.2(WDR35):c.1415G>A(p.Arg472Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000867 in 1,614,074 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: WDR35 NM_001006657.2 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 4.96

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-19953852-C-T is Pathogenic according to our data. Variant chr2-19953852-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 437865.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.26001137).. Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WDR35	NM_001006657.2	c.1415G>A	p.Arg472Gln	missense_variant	13/28	ENST00000345530.8
WDR35	NM_020779.4	c.1382G>A	p.Arg461Gln	missense_variant	12/27	ENST00000281405.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WDR35	ENST00000345530.8	c.1415G>A	p.Arg472Gln	missense_variant	13/28	1	NM_001006657.2	A1
WDR35	ENST00000281405.9	c.1382G>A	p.Arg461Gln	missense_variant	12/27	1	NM_020779.4	P3

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152156 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000318 AC: 8 AN: 251424 Hom.: 0 AF XY: 0.0000221 AC XY: 3 AN XY: 135888

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000440

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000616 AC: 9 AN: 1461800 Hom.: 0 Cov.: 31 AF XY: 0.00000688 AC XY: 5 AN XY: 727184

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000328 AC: 5 AN: 152274 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74458

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000264

ExAC AF: 0.0000412 AC: 5

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Cranioectodermal dysplasia 2 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

Laboratorio de Citogenómica y Microarreglos, Universidad Autonoma de Nuevo Leon

Aug 27, 2017

WDR35 participates in the retrograde IFT associated to cell cilium assembly and maintenance mainly through formation (along with IFT43) of the IFT-A complex. Although homozygous and compound heterozygous mutations in this gene usually lead to heterogenous clinical features, they have also been related to the distinct CED2 (OMIM 613610) and SRTD7 (OMIM 614091) syndromes. CED2 main features are craniosynostosis, dolichocephaly, narrow rib cage, short limbs, brachydactyly, and ectodermal defects (e.g., sparse hair, and nail and dental anomalies) whereas SRTD7 includes constricted thoracic cage, short ribs, and shortened tubular bones. Most patients with any of these syndromes appear to show normal intelligence and have no brain anomalies; however, two patients with developmental delay -- one featuring cortical atrophy, lobe defects, and ventriculomegaly and the other mega cisterna magna and slight cortical atrophy -- have been reported. Next generation sequencing: We focused on homozygous variants with a population frequency <0.01% and predicted to be pathogenic, likely pathogenic or variant of uncertain significance (VUS) by the SIFT, PANTHER, Mutation Taster 2, PhD-SNP, PROVEAN, and PolyPhen-2 platforms. Sequence conservation was evaluated by PhyloP, PhastCons and GERP scores; while MuPro and CFSSP from ExPASy were used to predict changes in the protein secondary structure. Results: The WDR35 mutation c.1415G>A also was a homozygous missense variant resulting in p.Arg472Gln. The total read depth for this variant was 62x (GQX= 99). This variant has not yet been reported in NHLBI Exome Sequencing Project (ESP) or ClinVar databases; but ExAC browser reported five alleles (5/121400, 0.00004119) with the same but heterozygous variant. This change is predicted to be likely pathogenic by Polyphen-2, PANTHER and Mutation tasting 2, whereas analysis by PROVEAN, SIFT and PhD-SNP considered this substitution to be neutral. Conservation scores (PhastCons = 1, PhyloP = 4.78, and GERP = 5.65) indicate that this position is evolutionary conserved. Accordingly, CFSSP tool denoted introduction of a new α-helix into the putative protein β-propeller domain 2 predicting stability decreasing from such missense variant. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.055	T
BayesDel_noAF	Benign	-0.11
Cadd	Uncertain	25
Dann	Pathogenic	1.0
Eigen	Uncertain	0.29
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.88	D;D;D
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.26	T;T;T
MetaSVM	Uncertain	0.044	D
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-1.8	N;N;N
REVEL	Benign	0.21
Sift	Benign	0.13	T;T;T
Sift4G	Benign	0.38	T;T;T
Polyphen		0.99	D;P;.
Vest4		0.30
MVP		0.83
MPC		0.59
ClinPred		0.50	T
GERP RS		5.7
Varity_R		0.13
gMVP		0.39

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: rs200140363; hg19: chr2-20153613; COSMIC: COSV55601925; COSMIC: COSV55601925;