NM_001006657.2:c.3203A>C

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2PM5PP3_Strong

The NM_001006657.2(WDR35):​c.3203A>C​(p.Tyr1068Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,844 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y1068C) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)
Exomes š‘“: 6.8e-7 ( 0 hom. )

Consequence

WDR35
NM_001006657.2 missense

Scores

10
6
3

Clinical Significance

Not reported in ClinVar

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]

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: 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}.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.941

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
WDR35NM_001006657.2 linkc.3203A>C p.Tyr1068Ser missense_variant Exon 27 of 28 ENST00000345530.8 NP_001006658.1 Q9P2L0-1
WDR35NM_020779.4 linkc.3170A>C p.Tyr1057Ser missense_variant Exon 26 of 27 ENST00000281405.9 NP_065830.2 Q9P2L0-2
WDR35XM_011533007.3 linkc.1898A>C p.Tyr633Ser 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>C p.Tyr1068Ser missense_variant Exon 27 of 28 1 NM_001006657.2 ENSP00000314444.5 Q9P2L0-1
WDR35ENST00000281405.9 linkc.3170A>C p.Tyr1057Ser missense_variant Exon 26 of 27 1 NM_020779.4 ENSP00000281405.5 Q9P2L0-2

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.00000398
AC:
1
AN:
251262
Hom.:
0
AF XY:
0.00000736
AC XY:
1
AN XY:
135872
show subpopulations
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:
0.0000327
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461844
Hom.:
0
Cov.:
31
AF XY:
0.00000138
AC XY:
1
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:
0.0000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32
Asia WGS
AF:
0.000289
AC:
1
AN:
3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.24
BayesDel_addAF
Pathogenic
0.32
D
BayesDel_noAF
Pathogenic
0.32
CADD
Pathogenic
27
DANN
Uncertain
0.99
DEOGEN2
Benign
0.25
.;T
Eigen
Pathogenic
0.84
Eigen_PC
Pathogenic
0.80
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.97
D;D
M_CAP
Uncertain
0.19
D
MetaRNN
Pathogenic
0.94
D;D
MetaSVM
Uncertain
0.13
D
MutationAssessor
Pathogenic
3.2
.;M
PrimateAI
Uncertain
0.72
T
PROVEAN
Pathogenic
-8.6
D;D
REVEL
Pathogenic
0.80
Sift
Pathogenic
0.0
D;D
Sift4G
Uncertain
0.0030
D;D
Polyphen
1.0
D;D
Vest4
0.91
MutPred
0.80
.;Loss of helix (P = 0.079);
MVP
0.86
MPC
0.66
ClinPred
1.0
D
GERP RS
5.5
Varity_R
0.94
gMVP
0.79

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.020
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