rs1553322982

chr2-19974540-G-Cchr2-19974540-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001006657.2(WDR35):c.664C>G(p.Pro222Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,460,568 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. P222P) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: WDR35 NM_001006657.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.87

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WDR35	NM_001006657.2	c.664C>G	p.Pro222Ala	missense_variant	7/28	ENST00000345530.8
WDR35	NM_020779.4	c.664C>G	p.Pro222Ala	missense_variant	7/27	ENST00000281405.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WDR35	ENST00000345530.8	c.664C>G	p.Pro222Ala	missense_variant	7/28	1	NM_001006657.2	A1
WDR35	ENST00000281405.9	c.664C>G	p.Pro222Ala	missense_variant	7/27	1	NM_020779.4	P3
WDR35	ENST00000414212.5	c.664C>G	p.Pro222Ala	missense_variant, NMD_transcript_variant	7/28	5
WDR35	ENST00000445063.5	c.202C>G	p.Pro68Ala	missense_variant, NMD_transcript_variant	2/18	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1460568 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 726580

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: 0.00000180

Gnomad4 OTH exome AF: 0.0000332

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Cranioectodermal dysplasia 2;C3279792:Short-rib thoracic dysplasia 7 with or without polydactyly Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Feb 11, 2020

In summary, this variant is a novel missense change that is not predicted to affect protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a WDR35-related disease. This sequence change replaces proline with alanine at codon 222 of the WDR35 protein (p.Pro222Ala). The proline residue is highly conserved and there is a small physicochemical difference between proline and alanine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.050
Cadd	Benign	21
Dann	Benign	0.97
Eigen	Benign	-0.0024
Eigen_PC	Benign	0.20
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.88	D;D
M_CAP	Benign	0.0096	T
MetaRNN	Uncertain	0.43	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.0	M;M
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.68	T
PROVEAN	Uncertain	-3.4	D;D
REVEL	Benign	0.25
Sift	Benign	0.48	T;T
Sift4G	Benign	0.74	T;T
Polyphen		0.20	B;B
Vest4		0.62
MutPred		0.49		Loss of stability (P = 0.101);Loss of stability (P = 0.101);
MVP		0.46
MPC		0.13
ClinPred		0.90	D
GERP RS		5.3
Varity_R		0.21
gMVP		0.43

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: rs1553322982; hg19: chr2-20174301;