2-19974479-T-G

Variant names:

• chr2-19974479-T-G
• rs139543775
• NM_001006657.2:c.725A>C

Variant summary

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

The NM_020779.4(WDR35):​c.725A>C​(p.Glu242Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000687 in 1,456,358 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: WDR35 NM_020779.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.92

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 rank	MANE	Protein	UniProt
WDR35	NM_001006657.2	c.725A>C	p.Glu242Ala	missense_variant	Exon 7 of 28	ENST00000345530.8	NP_001006658.1
WDR35	NM_020779.4	c.725A>C	p.Glu242Ala	missense_variant	Exon 7 of 27	ENST00000281405.9	NP_065830.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WDR35	ENST00000345530.8	c.725A>C	p.Glu242Ala	missense_variant	Exon 7 of 28	1	NM_001006657.2	ENSP00000314444.5
WDR35	ENST00000281405.9	c.725A>C	p.Glu242Ala	missense_variant	Exon 7 of 27	1	NM_020779.4	ENSP00000281405.5
WDR35	ENST00000414212.5	n.725A>C		non_coding_transcript_exon_variant	Exon 7 of 28	5		ENSP00000390802.1
WDR35	ENST00000445063.5	n.260A>C		non_coding_transcript_exon_variant	Exon 2 of 18	2		ENSP00000390105.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000402 AC: 1 AN: 248464 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 134210

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000100

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: 6.87e-7 AC: 1 AN: 1456358 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 724112

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000385

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Benign	-0.0058	T
BayesDel_noAF	Benign	-0.25
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.15	.;T
Eigen	Uncertain	0.33
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	D;D
M_CAP	Benign	0.034	D
MetaRNN	Uncertain	0.63	D;D
MetaSVM	Benign	-0.90	T
MutationAssessor	Pathogenic	3.1	M;M
PrimateAI	Uncertain	0.62	T
PROVEAN	Pathogenic	-4.7	D;D
REVEL	Benign	0.19
Sift	Benign	0.039	D;D
Sift4G	Benign	0.34	T;T
Polyphen		0.47	P;B
Vest4		0.77
MutPred		0.46		Gain of sheet (P = 0.0049);Gain of sheet (P = 0.0049);
MVP		0.45
MPC		0.21
ClinPred		0.89	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.39
gMVP		0.71

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: rs139543775; hg19: chr2-20174240;