rs146130105

Variant names:

• chr2-19945876-G-A
• rs146130105
• NM_001006657.2:c.1788C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_020779.4(WDR35):​c.1755C>T​(p.Val585Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000229 in 1,613,924 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00013 (2 hom.)
• Consequence: WDR35 NM_020779.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.846
• Publications: 0 publications found

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]

WDR35 Gene-Disease associations (from GenCC):

• cranioectodermal dysplasia 2

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen, G2P, Ambry Genetics
• short-rib thoracic dysplasia 7 with or without polydactyly

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Orphanet
• cranioectodermal dysplasia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• short rib-polydactyly syndrome, Verma-Naumoff type

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.37).
• BP6: Variant 2-19945876-G-A is Benign according to our data. Variant chr2-19945876-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 471483.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.846 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00113 (172/152196) while in subpopulation AFR AF = 0.00395 (164/41544). AF 95% confidence interval is 0.00345. There are 0 homozygotes in GnomAd4. There are 79 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020779.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WDR35	NM_001006657.2	MANE Plus Clinical	c.1788C>T	p.Val596Val	synonymous	Exon 17 of 28	NP_001006658.1	Q9P2L0-1
	WDR35	NM_020779.4	MANE Select	c.1755C>T	p.Val585Val	synonymous	Exon 16 of 27	NP_065830.2	Q9P2L0-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WDR35	ENST00000345530.8	TSL:1 MANE Plus Clinical	c.1788C>T	p.Val596Val	synonymous	Exon 17 of 28	ENSP00000314444.5	Q9P2L0-1
	WDR35	ENST00000281405.9	TSL:1 MANE Select	c.1755C>T	p.Val585Val	synonymous	Exon 16 of 27	ENSP00000281405.5	Q9P2L0-2
	WDR35	ENST00000453014.1	TSL:1	c.393C>T	p.Val131Val	synonymous	Exon 5 of 10	ENSP00000404409.1	H0Y6C0

Frequencies

GnomAD3 genomes AF: 0.00113 AC: 172 AN: 152078 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00396

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000328

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.000374 AC: 94 AN: 251372 AF XY: 0.000228

Gnomad AFR exome AF: 0.00523

Gnomad AMR exome AF: 0.000174

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000135 AC: 197 AN: 1461728 Hom.: 2 Cov.: 31 AF XY: 0.000111 AC XY: 81 AN XY: 727168

African (AFR) AF: 0.00520 AC: 174 AN: 33476

American (AMR) AF: 0.000157 AC: 7 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39684

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111892

Other (OTH) AF: 0.000232 AC: 14 AN: 60392

GnomAD4 genome AF: 0.00113 AC: 172 AN: 152196 Hom.: 0 Cov.: 32 AF XY: 0.00106 AC XY: 79 AN XY: 74392

African (AFR) AF: 0.00395 AC: 164 AN: 41544

American (AMR) AF: 0.000327 AC: 5 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10582

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67990

Other (OTH) AF: 0.00142 AC: 3 AN: 2108

Alfa AF: 0.000931 Hom.: 0

Bravo AF: 0.00136

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Cranioectodermal dysplasia 2;C3279792:Short-rib thoracic dysplasia 7 with or without polydactyly (1)
-	-	1	not specified (1)
-	-	1	WDR35-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.37
CADD	Benign	7.0
DANN	Benign	0.74
PhyloP100		0.85
Mutation Taster		=98/2	polymorphism

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

Other links and lift over

dbSNP: rs146130105; hg19: chr2-20145637;