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
Consequence
NM_020779.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
WDR35 | NM_001006657.2 | c.3203A>G | p.Tyr1068Cys | missense_variant | Exon 27 of 28 | ENST00000345530.8 | NP_001006658.1 | |
WDR35 | NM_020779.4 | c.3170A>G | p.Tyr1057Cys | missense_variant | Exon 26 of 27 | ENST00000281405.9 | NP_065830.2 | |
WDR35 | XM_011533007.3 | c.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 |
---|---|---|---|---|---|---|---|---|---|---|
WDR35 | ENST00000345530.8 | c.3203A>G | p.Tyr1068Cys | missense_variant | Exon 27 of 28 | 1 | NM_001006657.2 | ENSP00000314444.5 | ||
WDR35 | ENST00000281405.9 | c.3170A>G | p.Tyr1057Cys | missense_variant | Exon 26 of 27 | 1 | NM_020779.4 | ENSP00000281405.5 |
Frequencies
GnomAD3 genomes AF: 0.0000263 AC: 4AN: 152014Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000796 AC: 2AN: 251262Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135872
GnomAD4 exome AF: 0.00000752 AC: 11AN: 1461844Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3AN XY: 727222
GnomAD4 genome AF: 0.0000263 AC: 4AN: 152014Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74276
ClinVar
Submissions by phenotype
Cranioectodermal dysplasia 2 Pathogenic:1Uncertain:1
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. -
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not specified Pathogenic:1
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Inborn genetic diseases Pathogenic:1
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
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at