2-19911095-G-A

Position:

• chr2-19911095-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_020779.4(WDR35):​c.*2463C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0836 in 152,138 control chromosomes in the GnomAD database, including 745 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.084 (745 hom., cov: 32)
  • Exomes 𝑓: 0.25 (0 hom.)
• Consequence: WDR35 NM_020779.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.00200

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 2-19911095-G-A is Benign according to our data. Variant chr2-19911095-G-A is described in ClinVar as [Benign]. Clinvar id is 333335.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.222 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
WDR35	NM_001006657.2	c.*2463C>T		3_prime_UTR_variant	28/28	ENST00000345530.8	NP_001006658.1
WDR35	NM_020779.4	c.*2463C>T		3_prime_UTR_variant	27/27	ENST00000281405.9	NP_065830.2
WDR35	XM_011533007.3	c.*2463C>T		3_prime_UTR_variant	17/17		XP_011531309.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
WDR35	ENST00000345530	c.*2463C>T		3_prime_UTR_variant	28/28	1	NM_001006657.2	ENSP00000314444.5
WDR35	ENST00000281405	c.*2463C>T		3_prime_UTR_variant	27/27	1	NM_020779.4	ENSP00000281405.5

Frequencies

GnomAD3 genomes AF: 0.0836 AC: 12712 AN: 152016 Hom.: 745 Cov.: 32

Gnomad AFR AF: 0.0206

Gnomad AMI AF: 0.0736

Gnomad AMR AF: 0.0945

Gnomad ASJ AF: 0.108

Gnomad EAS AF: 0.232

Gnomad SAS AF: 0.139

Gnomad FIN AF: 0.114

Gnomad MID AF: 0.0506

Gnomad NFE AF: 0.0986

Gnomad OTH AF: 0.0882

GnomAD4 exome AF: 0.250 AC: 1 AN: 4 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 2

Gnomad4 NFE exome AF: 0.500

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0836 AC: 12712 AN: 152134 Hom.: 745 Cov.: 32 AF XY: 0.0866 AC XY: 6439 AN XY: 74372

Gnomad4 AFR AF: 0.0205

Gnomad4 AMR AF: 0.0943

Gnomad4 ASJ AF: 0.108

Gnomad4 EAS AF: 0.233

Gnomad4 SAS AF: 0.139

Gnomad4 FIN AF: 0.114

Gnomad4 NFE AF: 0.0986

Gnomad4 OTH AF: 0.0873

Alfa AF: 0.0978 Hom.: 1671

Bravo AF: 0.0791

Asia WGS AF: 0.165 AC: 572 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Cranioectodermal dysplasia 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Short-rib thoracic dysplasia 7 with or without polydactyly Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	1.1
DANN	Benign	0.32

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: rs3731661; hg19: chr2-20110856;