NM_001006657.2:c.2997+10C>A

Variant names:

• chr2-19931259-G-T
• rs201207790
• NM_001006657.2:c.2997+10C>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001006657.2(WDR35):​c.2997+10C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000373 in 1,605,054 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00029 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00038 (1 hom.)
• Consequence: WDR35 NM_001006657.2 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:2
• Conservation: PhyloP100: 0.122
• 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, STRONG Submitted by: G2P, PanelApp Australia, ClinGen, Ambry Genetics
• short-rib thoracic dysplasia 7 with or without polydactyly

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Orphanet, Labcorp Genetics (formerly Invitae)
• 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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001006657.2. 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.2997+10C>A		intron	N/A	NP_001006658.1
	WDR35	NM_020779.4	MANE Select	c.2964+10C>A		intron	N/A	NP_065830.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WDR35	ENST00000345530.8	TSL:1 MANE Plus Clinical	c.2997+10C>A		intron	N/A	ENSP00000314444.5
	WDR35	ENST00000281405.9	TSL:1 MANE Select	c.2964+10C>A		intron	N/A	ENSP00000281405.5
	WDR35	ENST00000968993.1		c.2892+10C>A		intron	N/A	ENSP00000639052.1

Frequencies

GnomAD3 genomes AF: 0.000293 AC: 43 AN: 146688 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000506

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000682

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: 0.000584

Gnomad OTH AF: 0.000499

GnomAD2 exomes AF: 0.000168 AC: 42 AN: 250200 AF XY: 0.000148

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000579

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000470

Gnomad NFE exome AF: 0.000327

Gnomad OTH exome AF: 0.000328

GnomAD4 exome AF: 0.000382 AC: 557 AN: 1458256 Hom.: 1 Cov.: 35 AF XY: 0.000323 AC XY: 234 AN XY: 725522

African (AFR) AF: 0.0000300 AC: 1 AN: 33378

American (AMR) AF: 0.0000672 AC: 3 AN: 44668

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26040

East Asian (EAS) AF: 0.00 AC: 0 AN: 39482

South Asian (SAS) AF: 0.00 AC: 0 AN: 86040

European-Finnish (FIN) AF: 0.0000573 AC: 3 AN: 52374

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5750

European-Non Finnish (NFE) AF: 0.000467 AC: 519 AN: 1110310

Other (OTH) AF: 0.000515 AC: 31 AN: 60214

GnomAD4 genome AF: 0.000286 AC: 42 AN: 146798 Hom.: 0 Cov.: 32 AF XY: 0.000337 AC XY: 24 AN XY: 71284

African (AFR) AF: 0.0000505 AC: 2 AN: 39610

American (AMR) AF: 0.0000681 AC: 1 AN: 14686

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3418

East Asian (EAS) AF: 0.00 AC: 0 AN: 4974

South Asian (SAS) AF: 0.00 AC: 0 AN: 4604

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9542

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 276

European-Non Finnish (NFE) AF: 0.000569 AC: 38 AN: 66760

Other (OTH) AF: 0.000493 AC: 1 AN: 2028

Alfa AF: 0.000454 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	2.0
DANN	Benign	0.48
PhyloP100		0.12

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: rs201207790; hg19: chr2-20131020;