rs1191778

Variant names:

• chr2-19931318-T-C
• rs1191778
• NM_001006657.2:c.2948A>G

Your query was ambiguous. Multiple possible variants found:

• chr2-19931318-T-C
• chr2-19931318-T-A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_020779.4(WDR35):​c.2915A>G​(p.Glu972Gly) variant causes a missense change. The variant allele was found at a frequency of 0.367 in 1,612,832 control chromosomes in the GnomAD database, including 114,307 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.31 (8350 hom., cov: 31)
  • Exomes 𝑓: 0.37 (105957 hom.)
• Consequence: WDR35 NM_020779.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: 3.85
• Publications: 42 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0037181973).
• BP6: Variant 2-19931318-T-C is Benign according to our data. Variant chr2-19931318-T-C is described in ClinVar as Benign. ClinVar VariationId is 167844.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.398 is higher than 0.05.

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.2948A>G	p.Glu983Gly	missense	Exon 25 of 28	NP_001006658.1	Q9P2L0-1
	WDR35	NM_020779.4	MANE Select	c.2915A>G	p.Glu972Gly	missense	Exon 24 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.2948A>G	p.Glu983Gly	missense	Exon 25 of 28	ENSP00000314444.5	Q9P2L0-1
	WDR35	ENST00000281405.9	TSL:1 MANE Select	c.2915A>G	p.Glu972Gly	missense	Exon 24 of 27	ENSP00000281405.5	Q9P2L0-2
	WDR35	ENST00000968993.1		c.2843A>G	p.Glu948Gly	missense	Exon 23 of 26	ENSP00000639052.1

Frequencies

GnomAD3 genomes AF: 0.312 AC: 47265 AN: 151702 Hom.: 8353 Cov.: 31

Gnomad AFR AF: 0.155

Gnomad AMI AF: 0.345

Gnomad AMR AF: 0.345

Gnomad ASJ AF: 0.421

Gnomad EAS AF: 0.0990

Gnomad SAS AF: 0.222

Gnomad FIN AF: 0.396

Gnomad MID AF: 0.443

Gnomad NFE AF: 0.402

Gnomad OTH AF: 0.340

GnomAD2 exomes AF: 0.337 AC: 84770 AN: 251262 AF XY: 0.338

Gnomad AFR exome AF: 0.150

Gnomad AMR exome AF: 0.361

Gnomad ASJ exome AF: 0.423

Gnomad EAS exome AF: 0.0979

Gnomad FIN exome AF: 0.394

Gnomad NFE exome AF: 0.404

Gnomad OTH exome AF: 0.370

GnomAD4 exome AF: 0.373 AC: 545403 AN: 1461012 Hom.: 105957 Cov.: 47 AF XY: 0.371 AC XY: 269614 AN XY: 726840

African (AFR) AF: 0.146 AC: 4884 AN: 33454

American (AMR) AF: 0.362 AC: 16167 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.415 AC: 10825 AN: 26108

East Asian (EAS) AF: 0.0948 AC: 3747 AN: 39546

South Asian (SAS) AF: 0.234 AC: 20205 AN: 86240

European-Finnish (FIN) AF: 0.392 AC: 20917 AN: 53336

Middle Eastern (MID) AF: 0.372 AC: 2144 AN: 5760

European-Non Finnish (NFE) AF: 0.400 AC: 445000 AN: 1111508

Other (OTH) AF: 0.356 AC: 21514 AN: 60352

GnomAD4 genome AF: 0.311 AC: 47255 AN: 151820 Hom.: 8350 Cov.: 31 AF XY: 0.307 AC XY: 22778 AN XY: 74172

African (AFR) AF: 0.154 AC: 6394 AN: 41472

American (AMR) AF: 0.344 AC: 5248 AN: 15248

Ashkenazi Jewish (ASJ) AF: 0.421 AC: 1458 AN: 3466

East Asian (EAS) AF: 0.0986 AC: 509 AN: 5162

South Asian (SAS) AF: 0.223 AC: 1075 AN: 4818

European-Finnish (FIN) AF: 0.396 AC: 4153 AN: 10482

Middle Eastern (MID) AF: 0.459 AC: 135 AN: 294

European-Non Finnish (NFE) AF: 0.402 AC: 27262 AN: 67860

Other (OTH) AF: 0.335 AC: 706 AN: 2106

Alfa AF: 0.371 Hom.: 47917

Bravo AF: 0.305

TwinsUK AF: 0.406 AC: 1506

ALSPAC AF: 0.417 AC: 1606

ESP6500AA AF: 0.161 AC: 709

ESP6500EA AF: 0.403 AC: 3463

ExAC AF: 0.332 AC: 40318

Asia WGS AF: 0.157 AC: 549 AN: 3476

EpiCase AF: 0.407

EpiControl AF: 0.411

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	3	Cranioectodermal dysplasia 2 (3)
-	-	2	Short-rib thoracic dysplasia 7 with or without polydactyly (2)
-	-	1	Cranioectodermal dysplasia 2;C3279792:Short-rib thoracic dysplasia 7 with or without polydactyly (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.14	T
Eigen	Benign	0.021
Eigen_PC	Benign	0.014
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.80	T
MetaRNN	Benign	0.0037	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		3.8
PrimateAI	Benign	0.45	T
PROVEAN	Uncertain	-3.2	D
REVEL	Benign	0.22
Sift	Benign	0.077	T
Sift4G	Benign	0.068	T
Polyphen		0.35	B
Vest4		0.13
MPC		0.33
ClinPred		0.047	T
GERP RS		4.8
Varity_R		0.11
gMVP		0.32
Mutation Taster		=84/16	polymorphism (auto)

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: rs1191778; hg19: chr2-20131079; COSMIC: COSV55601256; COSMIC: COSV55601256;